Ppar agonists and methods of use thereof

ABSTRACT

Provided herein are deuterated compounds and compositions useful in increasing PPARδ activity. The compounds have a formula 
     
       
         
         
             
             
         
       
     
     where L 5  comprises at least one deuterium. Exemplary species include 
     
       
         
         
             
             
         
       
     
     The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/022,578, filed on Jun. 28, 2018, which is a divisional of U.S.application Ser. No. 15/482,385, filed on Apr. 7, 2017, which is acontinuation of International Application No. PCT/US2015/053674, filedon Oct. 2, 2015, which claims the benefit of the earlier filing date ofU.S. Provisional Application No. 62/061,547, filed on Oct. 8, 2014, thecontents of which are incorporated herein by reference in its entirety.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under DK057978-32awarded by the National Institutes of Health. The government has certainrights in the invention.

FIELD

This application concerns agonists of peroxisome proliferator-activatedreceptors (PPAR), particularly PPAR delta (PPARδ), and methods for theiruse, such as to treat or prevent one or more PPARδ-related diseases.

BACKGROUND

Skeletal muscle is a mechanically and energetically active organ,supporting vital processes such as respiration and locomotion, and is amajor site of glucose and lipid metabolism. Therefore, maintainingproper muscle mass and function is critical. Muscle incurs damage due toa variety of insults such as use, disuse, aging and pathology. Whileskeletal muscle does not undergo rapid turn-over under normalconditions, upon being damaged, it is capable of executing a robustregenerative response through mobilization of its resident progenitorcells, the satellite cells (Moss F P, Leblond C P, Anat Rec 170:421-436(1970); Schultz E, Gibson M C, Champion T, J Exp Zool 206(3):451-6(1978); Snow M H, Cell Tissue Res 186(3):535-40 (1978)). Theself-renewal and differentiation capacity of the satellite cells havealluded to the archetypic “sternness,” but their fate seems largelycommitted (Sinanan A C M, Buxton P G, Lewis M P, Bio Cell 98:203-214(2006); Beauchamp J R et al., J Cell Biol 151:1221-1234 (2000); StarkeyJ D et al., J Histochem Cytochem 59(1):33-46 (2011)). In an adult,satellite cells comprise less than 5% of total nuclei on a myofiber;nevertheless, based on their proliferation kinetics and capacity, thisis sufficient to regenerate an entire muscle (Schmalbruch H, HellhammerU, Anat Rec 189:169-176 (1977); Kelly A M, Dev Bio 65(1): 1-10 (1978);Gibson M C, Schultz E, Anat Rec 202(3):329-337 (1982); Bischoff R inMyology, Vol 1, eds Engel A G, Franzini-Armstrong C (McGraw-Hill, Inc.,New York), (1994); Zammit P S et al., Exp Cell Res 281:39-49 (2002)).

Upon injury, skeletal muscle responds to damage in three distinct butoverlapping phases: degeneration; regeneration; and finally remodeling(Charge S B P, Rudnicki M A, Physiol Rev 84:209-238 (2004)). Immediatelyfollowing the injury, inflammatory cells are recruited to the injurysite to promote degeneration of the damaged tissue through necrosis andphagocytosis (Tidball J G, Am J Physiol Regul Integr Comp Physio288:R345-353 (2005); McLennan I S, J Anat 188:17-28 (1996);Pimorady-Esfahani A, Grounds M D, McMenamin P G, Muscle Nerve 20:158-166(1997); Vierck J et al., Cell Bio Int 24:263-272 (2000); Arnold L etal., J Exp Med 204(5):1057-1069 (2007)). The subsequent regenerativephase is characterized by mobilization of satellite cells, whereby theprogenitor cells proliferate, differentiate and fuse to each other or tothe existing fibers to regenerate the muscle (Zammit P S in Skeletalmuscle repair and regeneration, eds Schiaffino S, Partridge T (Springer,Dordrecht (2008)). Finally, the contractile proteins are reassembled andfunction is restored during the remodeling phase.

SUMMARY

Provided herein, inter alia, are compounds and compositions comprisingsuch compounds that are useful for increasing PPAR activity,particularly PPARδ activity. Also disclosed are methods of using thedisclosed compositions for treating or preventing PPARδ related diseases(e.g., muscular diseases, demyelinating disease, vascular disease, andmetabolic diseases).

Certain disclosed embodiments concern compounds having a formula

With reference to this formula, ring A may be selected from acycloalkylene, heterocycloalkylene, arylene or heteroarylene; ring B isselected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkylene, heterocycloalkylene, arylene or heteroarylene; each R²independently is selected from deuterium, halogen, aryl, heteroaryl,aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino, amide,aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, or acyl;each R²² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl; n is from 0 to 5; m is from 0 to 4; X is O, NR³⁰, sulfonyl, or S;R³⁰ is selected from H or aliphatic, aryl, or cycloaliphatic; each L² isselected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—; R²³ andR²⁴ are each independently selected from H, deuterium, halogen,aliphatic, alkyl, —C(O)OR²⁵ or —C(O)NR²⁵R²⁶; R²⁵ and R²⁶ are eachindependently selected from hydrogen, aliphatic or alkyl; Z is selectedfrom R¹L¹C(O)— or a carboxyl bioisostere; L¹ is a bond or —NR³⁰—; R¹ ishydrogen, aliphatic, —OR^(1A), —NR^(1A)R^(1B), —C(O)R^(1A),—S(O)₂R^(1A), —C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or —C(O)NR^(1A)R^(1B);R^(1A), R^(1B) are each independently selected from hydrogen oraliphatic, typically aliphatic, alkyl; L⁵ is

R^(c1) and R^(c2) are each independently H, D or alkyl; R^(c3) isaliphatic or D; p is 0, 1 or 2; ring C is a 5- or 6-memberedheterocyclyl or a 5- or 6-membered heteroaryl; each L³ independently isselected from a bond, aliphatic, —C(O)—, alkylC(O)—, —C(O)alkyl-, orsulfonyl; L⁴ is selected from a bond, aliphatic, heteroaliphatic,arylene, heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴;R³ is selected from —OH, —OR^(3A), —NR^(3A)R^(3B), —C(O)R^(3A),—S(O)₂R^(3A), —C(O)OR^(3A), —S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B),aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, or R³ can be joined with an atom of ring B to form a fusedring system or may be joined with an atom of L³ to form a heterocyclicring system; and R^(3A) and R^(3B) are independently selected fromhydrogen or aliphatic. Also with reference to this formula at least oneof L³, L⁴ or R³ comprises at least one deuterium and one L³ is orcomprises a —C(O)— adjacent to the nitrogen atom, or at least one ofR^(c1) and R^(c2) is D.

In certain embodiments, ring A is selected from a C₃-C₈cycloalkylene,C₂-C₅heterocycloalkylene, C₆-C₁₀arylene or C₁-C₁₀heteroarylene, withparticular examples having ring A being selected from phenyl, pyridine,cyclopentane, cyclohexane, pyrazole, thiophene or isothiazole. Incertain embodiments, ring B is selected from C₃-C₈cycloalkylene,C₂-C₈heterocycloalkylene, C₆-C₁₀arylene or C₁-C₁₀heteroarylene. Inparticular examples, ring B is selected from phenyl, pyridine,thiophene, thiazole, pyrazole, oxazole, isoxazole, benzo[b]furan,indazole, piperidine, cyclohexane, piperidin-2-one, piperazine-2,5-dioneor quinazolin-4(3H)-one.

Certain disclosed compounds include carboxyl biostere functionalities,such as

where X⁷, Y⁷, and Z⁷ each independently is selected from N, CH₂ or CO;X⁸ is selected from O, S or NMe; and X⁹ is selected from O, N, NH, S, CHor CH₂.

More particular embodiments concern compounds having one or more of thefollowing formulas:

wherein X¹ is selected from carbon, nitrogen, or N-oxide;

wherein X¹ is selected from carbon, nitrogen, or N-oxide;

wherein Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

wherein Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

wherein X² is selected from a bond, carbon, oxygen, sulfur, or NR³⁰;

wherein each X³ independently is selected from nitrogen, carbon, NR³⁰,or oxo, and each Y independently is selected from carbon or NR³⁰;

where each X¹, X², X³, Y and Z¹ are as defined above.

In some embodiments of any of the prior compound formulas,-L³N(L⁴R³)L³-may be selected

from each R³¹ and R³² is independently selected from deuterium,hydrogen, aliphatic, heteroaliphatic, or any one of R³¹ and R³² can bejoined with an atom of R³ to form a heterocyclic or heteroaryl ringsystem, or can be joined with an atom of ring B to form a fused ringsystem; each p independently is 0 to 5; and at least one R³¹ or one R³²is deuterium, or one of L⁴ or R³ comprises at least one deuterium. Incertain embodiments, -L³N(L⁴R³)L³-is selected from

and R³² is selected from deuterium, hydrogen, aliphatic orheteroaliphatic.

In other embodiments, of the prior compound formulas, -L⁴R³ is selectedfrom

Also with reference to any of the prior compound formulas, in certainembodiments: R³ may be selected from aliphatic, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl; L², L³ and L⁴ eachindependently is a bond or alkylene; L⁴R³ is isopropyl; R² is furan-2-ylor furan-3-yl; L² may be selected from

or halogenated, versions thereof, particularly fluorinated compounds;R²² is selected from Cl, F, I, Br, alkyloxy, haloalkyloxy,cycloalkyloxy, cyano, haloalkyl, CD₃, OCD₃, aliphatic, alkyl, alkenyl,alkynyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl,particularly Br, F, methyl, trifluoromethyl, cyano, methoxy, cyclopropylor azetidine; R² is selected from Cl, F, I, Br, alkyloxy, haloalkyloxy,cycloalkyloxy, cyano, haloalkyl, CD₃, OCD₃, aliphatic, alkyl, alkenyl,alkynyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl; n isfrom 2 to 4; two adjacent R² groups may form a fused ring system withring B, with particular compounds having R² selected from bromo, fluoro,methyl, trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino,acetyl, methanesulfonyl, cyano, cyclopropoxy, phenyl, furan-2-yl,furan-3-yl, thiophen-2-yl, thiophen-3-yl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-n-butylphenyl, 4-n-propylphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl,3,5-dimethylphenyl, 3-pyridyl, 4-pyridyl, naphthalen-1-yl,naphthalen-2-yl, (1,1′-biphenyl)-2-yl, pyrrolidin-1-yl,3-(furan-3-yl)phenyl,

In some embodiments, the compound has a formula

With reference to these formulas, R^(c3) may be alkyl or CX₃, where X ishalogen, such as with CF₃. In some embodiments, ring C is a 5-memberedheterocycle, and may be selected from imidazole, pyrazole, pyrrole,triazole, tetrazole, thiazole, isothiazole, thiadiazole, oxazole,isoxazole, oxadiazole, imidazoline, pyrrolidine, thiazoline oroxazoline. In certain embodiments, the

moiety or the

moiety is selected from

Pharmaceutical compositions also are disclosed. Particular embodimentscomprise a pharmaceutically acceptable excipient and one or more of thedisclosed compounds.

A method of activating PPARδ also is disclosed. For certain embodiments,the method comprises contacting a PPARδ protein with an effective amountof one or more disclosed compounds, or a pharmaceutical compositioncomprising one or more disclosed compounds, thereby activating the PPARδprotein. The PPARδ protein may be present in a subject, whereincontacting comprises administering the one or more compounds to thesubject. Activating the PPARδ protein within the subject can increase ormaintain muscle mass or muscle tone in the subject.

Another embodiment comprises treating a PPARδ-related disease orcondition in a subject by administering to the subject in need thereof atherapeutically effective amount of one or more disclosed compounds, ora pharmaceutical composition comprising the compound(s). For certainembodiments, administering a deuterated compound(s), or compositioncomprising a deuterated compound(s), provides substantially superiorbiological efficacy. Additional information concerning deuterationeffects is provided by “Analogs of Fexaramine and Methods of Making andUsing,” filed concurrently on Oct. 8, 2014, and listing Ronald Evans etal. as inventors. Each of these applications is incorporated herein byreference in its entirety. In certain embodiments, the PPARδ-relateddisease is a vascular disease; a muscular disease, such as a musculardystrophy disease, with particular examples including Duchenne musculardystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy,congenital muscular dystrophy, facioscapulohumeral muscular dystrophy,myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distalmuscular dystrophy, or Emery-Dreifuss muscular dystrophydemyelinatingdisease; a demyelinating disease, such as multiple sclerosis,Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease,encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, orGuillian-Barre syndrome; a muscle structure disorder, such as Bethlemmyopathy, central core disease, congenital fiber type disproportion,distal muscular dystrophy (MD), Duchenne & Becker M D, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, amuscle sodium channel disorder, myotonic chondrodystrophy, myotonicdystrophy, myotubular myopathy, nemaline body disease, oculopharyngealMD, or stress urinary incontinence; a neuronal activation disorder, suchas amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease,Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis,myasthenia gravis, nerve lesion, peripheral neuropathy, spinal muscularatrophy, tardy ulnar nerve palsy, or toxic myoneural disorder; a musclefatigue disorder, such as chronic fatigue syndrome, diabetes type I orII, glycogen storage disease, fibromyalgia, Friedreich's ataxia,intermittent claudication, lipid storage myopathy, MELAS,mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy; the musclemass disorder is cachexia, cartilage degeneration, cerebral palsy,compartment syndrome, critical illness myopathy, inclusion bodymyositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, orsystemic lupus erythematosus; a mitochondrial disease, such as Alpers'sDisease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-SayraSyndrome (KSS), Leber Hereditary Optic Neuropathy (LHON),MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, andstroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiberdisease, NARP-neurogenic muscle weakness, ataxia, and retinitispigmentosa, or Pearson Syndrome; a beta oxidation disease, such assystemic carnitine transporter, carnitine palmitoyltransferase (CPT) IIdeficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD)deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoAdehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase(SCAD) deficiency or riboflavin-responsive disorders of β-oxidation(RR-MADD); a metabolic disease, such as hyperlipidemia, dyslipidemia,hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia,LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDLhyperproteinemia, dyslipoproteinemia, apolipoprotein A-Ihypoproteinemia, atherosclerosis, disease of arterial sclerosis, diseaseof cardiovascular systems, cerebrovascular disease, peripheralcirculatory disease, metabolic syndrome, syndrome X, obesity, diabetes,type I or type II, hyperglycemia, insulin resistance, impaired glucosetolerance, hyperinsulinism, diabetic complication, cardiacinsufficiency, cardiac infarction, cardiomyopathy, hypertension,Non-alcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis(NASH), thrombus, Alzheimer disease, neurodegenerative disease,demyelinating disease, multiple sclerosis, adrenal leukodystrophy,dermatitis, psoriasis, acne, skin aging, trichosis, inflammation,arthritis, asthma, hypersensitive intestine syndrome, ulcerativecolitis, Crohn's disease, or pancreatitis; a cancer, such as a cancer ofthe colon, large intestine, skin, breast, prostate, ovary, or lung; avascular disease, such as peripheral vascular insufficiency, peripheralvascular disease, intermittent claudication, peripheral vascular disease(PVD), peripheral artery disease (PAD), peripheral artery occlusivedisease (PAOD), or peripheral obliterative arteriopathy; an ocularvascular disease, such as age-related macular degeneration (AMD),stargardt disease, hypertensive retinopathy, diabetic retinopathy,retinopathy, macular degeneration, retinal haemorrhage, or glaucoma; ora muscular eye disease, such as strabismus, progressive externalophthalmoplegia, esotropia, exotropia, a disorder of refraction andaccommodation, hypermetropia, myopia, astigmatism, anisometropia,presbyopia, disorders of accommodation, or internal ophthalmoplegia.

For certain disclosed method embodiments, the subject is a sedentary orimmobilized subject. In other embodiments, the subject can be anexercising subject.

For disclosed embodiments, administering may comprise intraarticular,intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, oral, topical, intrathecal, inhalational, transdermal,rectal administration, or any combination thereof. The one or morecompounds are administered to the subject at an effective dose, such asa dose of from greater than 0 mg/kg, such as from about 1 mg/kg to about20 mg/kg, or from about 2 mg/kg to about 10 mg/kg, with certainembodiments being administered at a dose of from about 2 mg/kg to about5 mg/kg.

The foregoing and other objects and features of the disclosure willbecome more apparent from the following detailed description, whichproceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawings will be provided by the Office upon request and paymentof the necessary fee.

FIGS. 1A and 1B are bar graphs showing recovery of damaged muscle fibersafter injury. The number of muscle fibers of a specified size (binedinto 50 μm² area bins) is reported for wildtype (WT) and VP16-PPARδ (TG)mice 5 days (FIG. 1A) and 7 days (FIG. 1B) after injury. All error barsare SEM. *P<0.05; **P<0.01; ***P<0.001.

FIGS. 1C-1F show that VP16-PPARδ transgenic animals exhibit acceleratedmuscle regeneration after acute injury. All error bars are SEM.

FIG. 1C provides Evans Blue stains of transverse sections of tibialisanterior (TA) muscle of WT and TG animals 5 days after the injury.Damaged fibers are stained by dye.

FIG. 1D provides quantitation of the proportion of stained area over thetotal cross-sectional area (CSA) of TA 5 days after the injury (n=5;**P<0.01).

FIG. 1E provides quantification of Evans Blue stain at 12 hours afterinjury (n=3).

FIG. 1F provides quantification of Evans Blue stain at 36 hours afterinjury (n=3).

FIGS. 1G-1J illustrate VP16-PPARδ transgenic animals that exhibitaccelerated muscle regeneration after acute injury. All error bars areSEM. *P<0.05; **P<0.01; ***P<0.001; n.s.=not significant.

FIG. 1G provides H&E stained transverse sections of injured tibialisanterior (TA) muscle from wildtype (WT) and transgenic (TG) animals.Images are representative from 3, 5 and 7 days after injury.Arrows=regenerating fibers with centralized nuclei. Arrowheads=hollowedremains of basal lamina. Asterisks=uninjured fibers.

FIG. 1H illustrates the average number of regenerating fibers per field.

FIG. 1I illustrates the average CSA of regenerating myofiber (n=5 forday 5; n=11 for day 7).

FIG. 1J illustrates the average CSA of regenerating myofiber, 21 daysafter injury (n=5).

FIGS. 2A-E illustrate that PPARδ activation promotes a temporal shift ofthe gene expression profile associated with the regenerative process.*P<0.05. All error bars are SEM.

FIG. 2A provides a GO classification of injury-specific upregulatedgenes in VP16-PPARδ (TG) compared to wildtype TA muscle (n=3).

FIG. 2B shows the relative expression of specific genes associated withregeneration in VP16-PPARδ (TG) compared to wildtype TA muscle.

FIG. 2C is a graph of relative expression versus days post injury,illustrating post injury temporal gene expression profiles ofinflammatory marker CD68, measured by QPCR (n=5).

FIG. 2D is a graph of relative expression versus days post injury,illustrating post injury temporal gene expression profiles of a myogenicmarker MyoD by Q-PCR (n=5).

FIG. 2E is a bar graph showing the Myh8 mRNA levels in control,uninjured and injured wildtype (WT) and VP16-PPARδ (TG) mice 5 days postinjury (n>5).

FIGS. 3A-3G illustrate that PPARδ promotes micro-vascularization throughthe regulation of FGF1a. *P<0.05; **P<0.01. All error bars are SEM.

FIG. 3A provides immunofluorescence staining for CD31 on transversesections of uninjured tibialis anterior (TA) muscle from WT and TGanimals.

FIG. 3B provides quantification of CD31 positive capillary numbers fromuninjured tibialis anterior (TA) muscle from WT and TG animals (n=4).

FIG. 3C illustrates the FGF1a mRNA level in TA of WT and TG by QPCR(n=5).

FIG. 3D provides a Western blot showing increased FGF1 in the VP16-PPARδ(TG) mice compared to wildtype mice (GAPDH western blot included as aloading control).

FIG. 3E provides immunofluorescence staining for CD31 positivecapillaries on transverse sections of TA from WT and TG animals 5 daysafter the injury (n=3).

FIG. 3F provides quantification for CD31 positive capillaries ontransverse sections of TA, 5 days after the injury (n=3).

FIG. 3G shows the ligand-dependent induction of FGF1a by PPARδ. Resultsof luciferase reporter assays of the FGF1a promoter co-transfected withPPARδ with or without the ligand, GW501516.

FIG. 4A-4E illustrate that the skeletal muscle specific activation ofPPARδ increases the quiescent satellite cell pool. All error bars areSEM. *P<0.05; **P<0.01.

FIG. 4A provides digital images of isolated myofibers from lateralgastrocnemius of 8-week-old nestin reporter mice with or withoutVP16-PPARδ transgene. The top panel shows the GFP fluorescence ofnestin-positive satellite cells, the middle panel shows DAPI staining ofall cell nuceli, and the overlay of the GFP fluorescence and DAPIstaining is shown in the bottom panel.

FIG. 4B is a bar graph showing quantification of GFP+ satellite cellsper unit length of myofiber in nestin-GFP mice (WT) and nestin-GFP micecrossed to the VP16-PPARδ mice, nestin-GFP;VP16-PPARδ mice (TG) (n=3).

FIG. 4C is a bar graph showing the proportion of BrdU positive nuclei at0.5, 1 and 2 days after injury in nestin-GFP mice (WT) and nestin-GFPmice crossed to the VP16-PPARδ mice, nestin-GFP;VP16-PPARδ mice (TG)(n=5).

FIG. 4D is a bar graph showing VP16 mRNA levels in whole TA compared toisolated satellite cells (SC) from nestin-GFP mice (WT) and nestin-GFPmice crossed to the VP16-PPARδ mice, nestin-GFP;VP16-PPARδ mice (TG).

FIG. 4E is a bar graph showing PPARδ mRNA levels in whole TA compared toisolated satellite cells (SC) from nestin-GFP mice (WT) and nestin-GFPmice crossed to the VP16-PPARδ mice, nestin-GFP;VP16-PPARδ mice (TG).

FIGS. 5A-5E illustrate that acute pharmacological activation of PPARδconfers regenerative advantage. *P<0.05; **P<0.01; ***P<0.001. All errorbars are SEM.

FIG. 5A is a series of bar graphs showing PPARδ target gene expressionin TA after a 9 day treatment with either vehicle or the PPARδ ligandGW501516 (n=6).

FIG. 5B provides digital images of transverse TA sections from vehicleor GW501516 treated mice showing Evans Blue dye uptake 5 days after theinjury.

FIG. 5C is a bar graph showing the proportions of Evans blue stainedarea (n=5) in the images of FIG. 5B.

FIG. 5D is a bar graph showing the percentage of BrdU positive nuclei 2days after injury in transverse TA sections from vehicle or GW501516treated mice (n=4).

FIG. 5E is a series of bar graphs showing relative gene expression ofTNFα and F4/80 in TA muscle from vehicle or GW501516 treated mice 3 daysafter injury, as measured by QPCR (n=6). The gene expression levels inthe uninjured, contralateral TA muscles are shown as the uninjuredcontrol.

FIG. 6 is a bar graph showing serum creatine kinase levels in wildtype(WT) and VP16-PPARδ (TG) transgenic animals after treadmill running toexhaustion.

FIG. 7A shows transverse sections of TA of wildtype (WT) and VP16-PPARδ(TG) animals 3 days after the injury. Staining of damaged fibers byEvans Blue.

FIG. 7B shows the time course of injury-dependent induction of PPARδ byQPCR (n=5).

FIG. 7C shows post injury temporal gene expression profile of theinflammatory marker TNFα in wildtype (WT, solid line) and VP16-PPARδ(TG, dashed line) after injury.

FIG. 7D shows induction of VEGFα in TA muscle, as measured by WesternBlot, in VP16-PPARδ (TG) compared to wildtype mice.

FIG. 7E shows quantification of VEGFα from a Western Blot.

FIG. 8A provides the increase in expression, shown as fold change, ofgenes involved in the Notch pathway in tibialis anterior (TA) musclefrom VP16-PPARδ (TG) compared to wildtype (WT) mice, as determined bymicroarray analysis (n=3).

FIG. 8B provides graphs of gene expression of Notch pathway componentsin tibialis anterior (TA) muscle from 2 months old VP16-PPARδ (TG) andwildtype (WT) mice, as determined by QPCR (n=5).

FIG. 8C provides graphs of gene expression of Notch pathway componentsin mice after 9 days of treatment with vehicle or the PPARδ ligandGW501516, as measured by QPCR (n=6).

FIG. 8D provides graphs of gene expression of Notch pathway componentsin tibialis anterior (TA) muscle from 12 months old VP16-PPARδ (TG) andwildtype (WT) mice, as determined by QPCR (n=3).

FIGS. 9A-9E are graphs showing pharmacokinetic data for severalcompounds at 3 mg/kg i.v. or 10 mg/kg p.o.

FIG. 9A are graphs showing the bioavailability of MA-0089 at 3 mg/kgi.v. or 10 mg/kg p.o. in mice.

FIG. 9B are graphs showing the bioavailability of MA-0011 at 3 mg/kgi.v. or 10 mg/kg p.o. in mice.

FIG. 9C are graphs showing the bioavailability of MA-0089 at 3 mg/kgi.v. or 10 mg/kg p.o. in mice.

FIG. 9D are graphs showing the bioavailability of GW501516 at 3 mg/kgi.v. or 10 mg/kg p.o. in rats.

FIG. 9E are graphs showing the bioavailability of GW501516 at 3 mg/kgi.v. and 10 mg/kg p.o. in mice.

FIGS. 10A and 10B are graphs showing relative guanines of free fattyacids in the brain (A) and liver (B) of AKO mice administered GW,compared to AKO mice not administered GW and wild-type mice.

FIG. 11A is a graph showing expression of mitochondrial fatty acidoxidation genes Cpt1a, Slc25a20, and Acadl in the livers of AKO miceadministered GW compared to AKO mice not administered GW.

FIG. 11B is a graph showing expression of mitochondrial fatty acidoxidation genes Cpt1b, Slc25a20, and Acadl in the skeletal muscle of AKOmice administered GW compared to AKO mice not administered GW.

FIGS. 12A and 12B are graphs showing the relative quanities of totalfatty acids in the liver (A) and skeletal muscle (B) of AKO miceadministered GW compared to AKO mice not administered GW.

DETAILED DESCRIPTION I. Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. For example, the term “comprising a PPARδagonist” includes single or plural PPARδ agonists and is consideredequivalent to the phrase “comprising at least one PPARδ agonist.” Theterm “or” refers to a single element of stated alternative elements or acombination of two or more elements, unless the context clearlyindicates otherwise. As used herein, “comprises” means “includes.” Thus,“comprising A or B,” means “including A, B, or A and B,” withoutexcluding additional elements. Dates of GenBank® Accession Nos. referredto herein are the sequences available at least as early as October 2014.All references, including patents and patent applications, and GenBank®Accession numbers cited herein, are incorporated by reference.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

All groups stated herein are understood to include both substituted andunsubstituted forms unless specifically stated otherwise, or contextindicates otherwise. “Substituted” means that one or more hydrogen atomsof the specified group or moiety is each, independently of one another,replaced with the same or a different non-hydrogen substituent.

In some embodiments, exemplary substituent groups can include thoselisted below:

Substituents for aliphatic, heteroaliphatic, cycloaliphatic and/orheterocycloaliphatic moieties can be one or more of a variety of groupsselected from, but not limited to, aliphatic, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl,—OR′, oxo, ═NR′, ═N—OR′, —NR′R″, —SW, halogen, —SiR′R″R′″, —OC(O)R,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NRSO₂R′, —CN, and —NO₂ in a number ranging from zero to (2m′+1) or (2 m′-1), where m′ is the total number of carbon atoms in suchmoiety. R′, R″, R′″, and R″″ each independently refer to hydrogen,aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, oraryl groups. In some embodiments, R′, R″, R′, and R″″ can independentlyrefer to aliphatic, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl groups. Whena compound includes more than one R′, R″, R′″, or R″″ group, forexample, each of the R′, R″, R′″, or R″″ groups can be independentlyselected relative to the remaining R′, R″, R′″, and R″″ group(s). Insome embodiments, when R′ and R″ are attached to the same or an adjacentatom, such as a nitrogen atom, they can be combined to form a cyclicstructure, such as a 4-, 5-, 6-, or 7-membered heterocyclic ring.

Substituents for aryl and heteroaryl groups may be selected from, forexample: aliphatic, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, —OR′, —NR′R″,—SR′, halogen, —SiR′R″R′″, —OC(O)R, —C(O)R, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R, —NR′—C(O)NR″R″, —NR″C(O)₂R′,—NR—C(NR′R″R″)═NR′″, —NR—C(NR′R″)═NR″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofpossible positions on the aromatic ring system; and where R′, R″, R′″,and R″″ are independently refer to hydrogen, aliphatic, heteroaliphatic,cycloaliphatic, heterocycloaliphatic, or aryl groups. In someembodiments, R′, R″, R′″, and R″″ can independently refer to alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, orheterocycloalkynyl groups. When a compound includes more than one R′,R″, R′″, or R″″ group, for example, each of the R′, R″, R′″, or R″″groups can be independently selected relative to the remaining R′, R″,R′″, and R″″ group(s).

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloaliphatic, or heterocycloaliphatic groups. Suchring-forming substituents are typically, though not necessarily,attached to a cyclic base structure. In some embodiments, thering-forming substituents are attached to adjacent members of the basestructure. For example, two ring-forming substituents can attached toadjacent atoms of a cyclic base structure to create a fused ringstructure. In other embodiments, the ring-forming substituents can beattached to a single atom of the base structure to create a spirocyclicstructure. In yet another embodiment, the ring-forming substituents areattached to non-adjacent atoms of the base structure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; such as the R and Sconfigurations for each asymmetric center, E and Z isomers for olefins,and/or the m and p configurations for each biaryl ring system.Therefore, single stereochemical isomers, as well as enantiomeric,diastereomeric, and atropisomeric mixtures of the present compounds arewithin the scope of the disclosure, as well as racemic mixtures. In someembodiments, the compounds disclosed herein are synthesized in or arepurified to be in substantially enantiopure form, such as in a 90%enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomericexcess or even in greater than a 99% enantiomeric excess, such as inenantiopure form.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon,are within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as, for example, tritium (³H), nitrogen(N¹⁵), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

The terms “a,” “an,” or “a(n),” when used in reference to a group ofsubstituents herein, mean at least one.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “alkyl,” means, unless otherwise stated, a straight (i.e.,unbranched), branched or cyclic saturated hydrocarbon chain, orcombination thereof, and can include di- and multivalent moieties,having the number of carbon atoms designated (for example, C₁-C₁₀includes alkyl groups comprising one to ten carbons). Examples of alkylgroups include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,(cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An “alkoxy” group is an alkylgroup comprising at least one oxygen atom in the chain. Alkyl groups mayalso comprise one or more isotopic variants, such as deuterium atoms inplace of one or more corresponding hydrogen atoms.

The term “aliphatic” refers to a hydrocarbon-based compound, or a moietythereof, and can include alkanes, alkenes, alkynes, including cyclicversions thereof, (cycloaliphatic or cyclicaliphatic such as cycloalkyl,cycloalkenyl and cycloalkynyl) and further including straight- and/orbranched-chain arrangements, and all stereo and positional isomers aswell. Unless expressly stated otherwise, an aliphatic group contains atleast one carbon atom. Aliphatic groups may also comprise one or moreisotopic variants, such as deuterium atoms in place of one or morecorresponding hydrogen atoms.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 10 carbon atoms, and in some embodiments 2 to 8 carbon atoms,and having at least 1 double bond. Such groups are exemplified, forexample, bi-vinyl, allyl, and but-3-en-1-yl. Included within this termare the cis and trans isomers or mixtures of these isomers, unlessotherwise specified. Examples of unsaturated alkyl groups include, butare not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and the higherhomologs and isomers. A person of ordinary skill in the art willunderstand that the olefin can be at any allowable position in analkenyl chain. The term “alkenylene” refers to a divalent moiety derivedfrom an alkenyl. Alkenyl groups may also comprise one or more isotopicvariants, such as deuterium atoms in place of one or more correspondinghydrogen atoms.

“Alkynyl,” by itself or as part of another substituent, refers tostraight chain or branched hydrocarbyl groups having from 2 to 10 carbonatoms, and in some embodiments 2 to 8 carbon atoms, and having at least1 site of triple bond unsaturation. Such groups are exemplified, forexample, by ethynyl, 1-propynyl and 2-propynyl. The term “alkynylene”refers to a divalent moiety derived from an alkynyl. Example alkynylgroups include ethynyl, 1- and 3-propynyl, 3-butynyl, and higherhomologs and isomers. Alkynyl groups may also comprise one or moreisotopic variants, such as deuterium atoms in place of one or morecorresponding hydrogen atoms.

The term “heteroaliphatic” refers to an aliphatic compound or grouphaving at least one heteroatom. For example, in some embodiments, one ormore carbon atoms has been replaced with an atom typically having atleast one lone pair of electrons, such as O, N, P, S, and Si.Heteroaliphatic compounds or groups may be branched or unbranched,cyclic or acyclic, and can include “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” or “heterocyclic” groups. Heteroaliphatic groupsmay also comprise one or more isotopic variants, such as deuterium atomsin place of one or more corresponding hydrogen atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight, branched or cyclicchain, or combinations thereof, consisting of at least one carbon atomand at least one heteroatom selected from the group consisting of O, N,P, Si, and S, and wherein the nitrogen and sulfur atoms may optionallybe oxidized, and the nitrogen heteroatom may optionally be quaternized.The heteroatom(s) 0, N, P, S, and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which the alkylgroup is attached to the remainder of the molecule. Examples include,but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —Si(CH₃)₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to twoheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.Heteroalkyl groups may also comprise one or more isotopic variants, suchas deuterium atoms in place of one or more corresponding hydrogen atoms.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, at least a divalent moietyderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). As described above, heteroalkyl groups, as used herein,include those groups that are attached to the remainder of the moleculethrough a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′,and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitationsof specific heteroalkyl groups, such as —NR′R″ or the like, it will beunderstood that the terms heteroalkyl and —NR′R″ are not redundant ormutually exclusive. Rather, the specific heteroalkyl groups are recitedto add clarity. Thus, the term “heteroalkyl” should not be interpretedherein as excluding specific heteroalkyl groups, such as —NR′R″ or thelike.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means atleast a divalent moiety derived from a cycloalkyl and heterocycloalkyl,respectively. Cycloalkyl and heterocycloalkyl groups may also compriseone or more one or more isotopic variants, such as deuterium atoms inplace of one or more corresponding hydrogen atoms.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl, including mixedhalogen-bearing substituents comprising two different halogens. Forexample, the term “halo(C₁-C₄)alkyl” includes, but is not limited to,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,4-chlorobutyl, 3-bromopropyl, and the like.

The term “amino,” refers to a chemical functional group —N(R¹)R¹¹ whereR¹ and R¹¹ are independently hydrogen, aliphatic, alkyl, heteroalkyl,haloalkyl, aliphatic, heteroaliphatic, aryl (such as phenyl or benzyl),heteroaryl, or other functionality. A “primary amino” group is —NH₂. Theterm “aminocarbonyl” refers to a chemical functional group —C(O)-amino,where amino is as defined herein. A primary aminocarbonyl is —CONH₂.

The term “cyano” refers to the chemical functional group —CN.

The term “carboxyl,” “carboxylic acid” or “carboxy” refers to thechemical functional group —CO₂H.

The term “carboxyl ester,” “carboxylic acid ester,” or “carboxy ester”refers to the chemical functional group —CO₂R where R is aliphatic,alkyl, heteroalkyl, haloalkyl, aliphatic, heteroaliphatic, aryl (such asphenyl or benzyl), heteroaryl, or other functionality.

The term “aminosulfonyl” refers to a chemical function group —SO₂-amino,where amino is as defined herein. A primary aminosulfonyl is —SO₂NH₂.

The term “acyl” means, unless otherwise stated, —C(O)R where R is aaliphatic, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, orheteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic moiety, such as an aromatic hydrocarbon substituent, which canbe a single ring or multiple rings (e.g., from 1 to 5, typically 1 to 3,rings) that are fused together (i.e., a fused ring aryl) or linkedcovalently. A fused ring aryl refers to multiple rings fused togetherwherein at least one of the fused rings is an aryl ring.

The term “heteroaryl” refers to aryl groups (or rings) that contain atleast one heteroatom, typically N, O, and S. For certain embodiments,heteroatoms, such as the nitrogen and sulfur atoms, are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Thus, theterm “heteroaryl” includes fused ring heteroaryl groups (e.g., multiplerings fused together wherein at least one of the fused rings is aheteroaromatic ring). A 5,6-fused ring heteroaryl refers to two ringsfused together, wherein one ring has 5 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. Likewise, a6,6-fused ring heteroaryl refers to two rings fused together, whereinone ring has 6 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylrefers to two rings fused together, wherein one ring has 6 members andthe other ring has 5 members, and wherein at least one ring is aheteroaryl ring. A heteroaryl group can be attached to the remainder ofa molecule through a carbon or heteroatom. Non-limiting examples of aryland heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,4-benzoxadiazolyle, 5-benzoxodiazole, benzofuran, benzofuranone,benzothiophene, indole, indoline, indolinone 3-quinolyl, and 6-quinolyl.Substituents for each of the above noted aryl and heteroaryl ringsystems are selected from the group of acceptable substituents describedbelow. “Arylene” and a “heteroarylene,” alone or as part of anothersubstituent, mean at least a divalent moiety derived from an aryl andheteroaryl, respectively.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose moieties in which an aryl group is attached to an aliphatic oralkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like)including those aliphatic or alkyl groups in which a carbon atom (e.g.,a methylene group) has been replaced by, for example, an oxygen atom(e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, andthe like).

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “sulfonyl,” as used herein, means a moiety having the formula—S(O₂)—R′, where R′ is an aliphatic, alkyl, aryl or heteroaryl, group asdefined above. R′ may have a specified number of carbons (e.g., “C₁-C₄alkylsulfonyl”).

The terms “carboxyl bioisosteric,” or “carboxyl bioisostere” refer to agroup with similar physical or chemical properties to a carboxyl groupthat produce broadly similar biological properties, but which may reducetoxicity or modify the activity of the compound, and may alter themetabolism of the compound. Exemplary carboxyl bioisosteres include, butare not limited to,

where X⁷, Y⁷, and Z⁷ are each independently selected from N, CH₂ or CO;

where X⁸ is selected from O, S or NMe;

where X⁹ is selected from O, N, S, CH or CH₂;

Additional carboxyl bioisosteric groups contemplated by the presentdisclosure include

The term “pharmaceutically acceptable salts” is meant to include saltsof active compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present disclosure containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable solvent.Examples of pharmaceutically acceptable base addition salts include, byway of example and without limitation, sodium salts, potassium salts,calcium salts, ammonium salts, organic amino salts, or magnesium salts,or a similar salt. When compounds of the present disclosure containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids, such as arginate and the like, andsalts of organic acids, like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present disclosure contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

Thus, the compounds provided herein can exist as salts withpharmaceutically acceptable acids. The present disclosure includes suchsalts. Examples of such salts include hydrohalides, such ashydrochlorides and hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (eg (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures),succinates, benzoates and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those of ordinary skillin the art.

The neutral forms of the compounds are in some examples regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present disclosure includes compounds ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds herein. Additionally, prodrugs canbe converted to the compounds of the present disclosure by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to the compounds of the present disclosure whenplaced in a transdermal patch reservoir with a suitable enzyme orchemical reagent.

Certain compounds provided herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present disclosure. Certain compounds provided herein canexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentdisclosure and are intended to be within the scope of the presentdisclosure.

The terms “administer,” “administering,” “administration,” and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

As used herein, the terms “co-administration,” “administered incombination with,” and their grammatical equivalents, are meant toencompass administration of two or more therapeutic agents to a singlesubject, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the one or morecompounds described herein will be co-administered with other agents.These terms encompass administration of two or more agents to thesubject so that both agents and/or their metabolites are present in thesubject at the same time. They include simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

The term “effective amount” or “therapeutically effective amount” refersto the amount of an active agent (such as one or more compounds providedherein alone, in combination, or potentially in combination with othertherapeutic agent(s)) sufficient to induce a desired biological result.That result may be amelioration or alleviation of the signs, symptoms,or causes of a disease, or any other desired alteration of a biologicalsystem. The term “therapeutically effective amount” is used herein todenote any amount of a therapeutic that causes an ameloriation,improvement and/or prevention in a disease condition. The amount canvary with the condition being treated, the stage of advancement of thecondition, and the type and concentration of formulation applied.Appropriate amounts in any given instance will be readily apparent tothose of ordinary skill in the art or capable of determination byroutine experimentation.

The terms “prevent,” “preventing” or “prevention,” and other grammaticalequivalents as used herein, include preventing additional symptoms,preventing the underlying metabolic causes of symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition and are intended to include prophylaxis. The terms furtherinclude achieving a prophylactic benefit. For prophylactic benefit, thecompositions are optionally administered to a subject at risk ofdeveloping a particular disease, to a subject reporting one or more ofthe physiological symptoms of a disease, or to a subject at risk ofreoccurrence of the disease. Preventing the disease can result in thedelay or prevention of development of one or more clinical symptoms ofthe disease by administration of a protective composition prior to theinduction of the disease; suppressing the disease, that is, causing theclinical symptoms of the disease not to develop by administration of aprotective composition after the inductive event but prior to theclinical appearance or reappearance of the disease.

“Inhibiting” the disease refers to arresting the development of clinicalsymptoms by administration of a protective composition after theirinitial appearance; preventing re-occurring of the disease and/orrelieving the disease, that is, causing the regression of clinicalsymptoms by administration of a protective composition after theirinitial appearance.

The terms “subject,” “individual,” or “patient,” are usedinterchangeably. These terms refer to a biological entity, such as avertebrate, including a mammal, for example a human. Mammals include,but are not limited to, murines, simians, humans, farm animals, sportanimals, and pets. Tissues, cells and their progeny of a biologicalentity obtained in vitro or cultured in vitro are also encompassed. Insome embodiments, the subject administered one or more of the compoundsprovided herein is a sedentary (such as one with no or irregularphysical activity, for example one who sits or remains inactive for mostof the day with little or no exercise) or immobilized subject (such as asubject confined to a wheelchair, hospital bed, and the like, or one whohas a body part in a cast, such as a leg or arm). In other embodiments,the subject administered one or more of the compounds provided herein isan ambulatory or exercised subject, such as a subject in rehabpotentially after surgery, or aged or obese subjects. In someembodiments, exercise can include low impact exercise, spanning fromonce or twice per day. Examples of low impact exercise can includeswimming and light to moderate resistance training.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable excipients includewater, NaCl, normal saline solutions, lactated Ringer's, normal sucrose,normal glucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with or interfere with the activity ofthe compounds provided herein. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are suitable for use withdisclosed compounds.

The term “preparation” is intended to include formulations of an activecompound with another material, such as an encapsulating material as acarrier to provide a capsule. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges canbe used as solid dosage forms suitable for oral administration.

The term “peroxisome proliferator-activated receptor delta (PPARδ)”refers to the PPARδ protein (or its coding or gene sequence), a memberof a subfamily of nuclear hormone receptors. Ligands of PPARδ canpromote myoblast proliferation after injury, such as injury to skeletalmuscle. PPARδ (OMIM 600409) sequences are publically available, forexample from GenBank® sequence database (e.g., accession numbersNP_001165289.1 (human, protein) NP 035275 (mouse, protein), NM_001171818(human, nucleic acid) and NM_011145 (mouse, nucleic acid)).

II. Compounds

Disclosed herein are embodiments of a compound having general Formula 1

With respect to Formula 1, L⁵ is

R^(c1) and R^(c2) are each independently H, D or alkyl, and at least oneof R^(c1) and R^(c2) is D; R^(c3) is aliphatic or D; p is 0, 1 or 2;ring C is a 5- or 6-membered heterocyclyl or a 5- or 6-memberedheteroaryl; each L³ independently is selected from a bond, aliphatic,—C(O)—, alkylC(O)—, —C(O)alkyl-, or sulfonyl, and at least one L³ is orcomprises a —C(O)— that forms an amide moiety with the nitrogen inFormula 1A; L⁴ is selected from a bond, aliphatic, heteroaliphatic,arylene, heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—;R³ is selected from —OH, —OR^(3A), —NR^(3A)R^(3B), —C(O)R^(3A),—S(O)₂R^(3A), —C(O)OR^(3A), —S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B),aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, or R³ can be joined with an atom of ring A ring B to form afused ring system or may be joined with an atom of L³ to form aheterocyclic ring system; and at least one of L³, L⁴ or R³ comprises atleast one deuterium; and R^(3A) and R^(3B) are independently selectedfrom hydrogen or aliphatic, typically alkyl.

Also with reference to Formula 1, ring A is selected from acycloaliphatic, cycloalkylene, heterocycloalkylene, arylene orheteroarylene. Further with respect to ring A, in certain embodimentswhen ring A is phenyl, the L⁵ group and the X-L²-Z group typically arepositioned ortho or para to each other. In further embodiments whereinring A is phenyl, the L⁵ group and the X-L²-Z are not positioned meta toeach other unless L⁵ forms a fused ring system with ring A. Exemplaryring A embodiments are illustrated below:

In an independent embodiment, ring A is selected from

Ring B is selected from aryl, heteroaryl, cycloaliphatic, cycloalkyl,heterocycloalkyl, cycloalkylene, heterocycloalkylene, arylene orheteroarylene. Exemplary ring B embodiments are illustrated below:

In an independent embodiment, ring B is selected from

Each R² independently is selected from hydrogen, deuterium, halogen,aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH,amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl,SO₃H, or acyl.

In some embodiments R² may be halogen selected from Cl, F, I, Br;heteroaliphatic selected from alkyloxy (e.g., O(CH₂)₀₋₅CH₃),haloalkyloxy (e.g., O(CH₂)₀₋₅CF₃, O(CH₂)₀₋₅CHF₂), cycloalkyloxy (e.g.,O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl), cyano,haloalkyl (e.g., CF₃), CD₃, OCD₃; aliphatic, selected from alkyl,alkenyl, alkynyl; amino selected from N(R³⁰)₂ wherein each R³⁰ may beselected from hydrogen, aliphatic, aryl, or cycloaliphatic; heterocyclicselected from piperidinyl, piperazinyl, pyrrolidinyl, 4H-pyranyl,4H-furanyl, 4H-thiophene, 4H-thiopyranyl, azetidinyl, oxetanyl,piperidinone, 4H-pyranone, 4H-furanone, 4H-pyrrolidone, 4H-thiopyranone,4H-thiophenone, and any such groups comprising one or more sites ofunsaturation; aryl selected from phenyl, naphthalene, anthracene, orphenanthracene; cycloaliphatic selected from cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, bicyclononane, bicycloheptane,and any such groups comprising one or more sites of unsaturation;heteroaryl selected from pyridinyl, furanyl, thiophene, pyrrole,oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiodiazole,diazole, triazole, or tetrazole. In some embodiments, at least two R²groups are present and adjacent to each other and join together to forma fused ring system with ring B. In such embodiments, each R² can beselected to form a fused heterocylic, cyclicaliphatic, heteroaryl, oraryl ring system. Exemplary R² groups are provided below:

With continued reference to Formula 1:

n is from 0 to 5;

m is from 0 to 4;

each R²² independently is selected from hydrogen, deuterium, halogen,aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH,amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl,SO₃H, or acyl. In some embodiments R²² may be halogen selected from Cl,Fl, I, Br; heteroaliphatic selected from alkyloxy (e.g., O(CH₂)₀₋₅CH₃),haloalkyloxy (e.g., O(CH₂)₀₋₅CF₃, O(CH₂)₀₋₅CHF 2), cycloalkyloxy (e.g.,O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl), cyano,haloalkyl (e.g., CF₃), CD₃, OCD₃; aliphatic, selected from alkyl,alkenyl, alkynyl; amino selected from N(R¹R¹¹)₂ wherein each R³⁰ may beselected from hydrogen, aliphatic, aryl, or cycloaliphatic; heterocyclicselected from piperidinyl, piperazinyl, pyrrolidinyl, 4H-pyranyl,4H-furanyl, 4H-thiophene, 4H-thiopyranyl, azetidinyl, oxetanyl,piperidinone, 4H-pyranone, 4H-furanone, 4H-pyrrolidone, 4H-thiopyranone,4H-thiophenone, and any such groups comprising one or more sites ofunsaturation; aryl selected from phenyl, naphthalene, anthracene, orphenanthracene; cycloaliphatic selected from cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, bicyclononane, bicycloheptane,and any such groups comprising one or more sites of unsaturation;heteroaryl, selected from pyridinyl, furanyl, thiophene, pyrrole,oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiodiazole,diazole, triazole, or tetrazole. Exemplary R²² groups are providedbelow:

X is O, NR³⁰, sulfonyl, or S, where R³⁰ is selected from H or aliphatic,aryl, or cycloaliphatic.

Each L² is selected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—, whereinR²³ and R²⁴ each independently is selected from H, deuterium, halogen,aliphatic, alkyl, —C(O)OR²⁵ or —C(O)NR²⁵R²⁶, wherein R²⁵ and R²⁶ eachindependently is hydrogen or aliphatic, alkyl. Exemplary L² groups areprovided below. In any of the embodiments disclosed herein for L², theL² group can be halogenated. In some embodiments, the L² group may befluorinated.

Z is selected from R¹L¹C(O)— or a carboxyl bioisostere, wherein L¹ is abond or —NR³⁰—, and R¹ is hydrogen, aliphatic, —OR′—NR^(1A)R^(1B),—C(O)R^(1A), —S(O)₂R^(1A), —C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or—C(O)NR^(1A)R^(1B), wherein R^(1A), R^(1B) each independently ishydrogen or aliphatic, alkyl, and R³⁰ is selected from H or aliphatic,aryl, or cycloaliphatic.

In some embodiments, Z is a carboxyl bioisostere, and in certainembodiments, Z is selected from

where X⁷, Y⁷, and Z⁷ each independently is selected from N, CH₂ or CO;X⁸ is selected from O, S or NMe; and X⁹ is selected from O, N, NH, S, CHor CH₂.

In an independent embodiment, Z is selected from

In some embodiments, L⁵ is

leading to compounds having a Formula 1A

wherein L³, L⁴ and R³ are as defined above with respect to Formula 1.

With respect to ring A, in some embodiments of Formula 1A, the L³ groupand the X-L²-Z group are positioned ortho to each other, leading tocompounds having Formula 2

wherein rings A and B, X, L², Z, R², R²², m, n, L³, L⁴ and R³ are asrecited above.

Also with reference to Formulas 1A and/or 2, the -L³N(L⁴R³)L³-group mayhave any of the following formulas, which may be incorporated in any ofthe general formulas provided herein.

With reference to these embodiments, each R³¹ and R³² is independentlyselected from hydrogen, deuterium, aliphatic, heteroaliphatic, or anyone of R³¹ and R³² may be joined with R³ to form a ring, such as afour-, five-, six-, or seven-membered ring system, which may besaturated or unsaturated, or may be joined with an atom of ring B toform a fused ring system, such as a 5-6 fused ring system, a 6-6 fusedring system, or a 6-5 fused ring system; and each p independently is 0,1, 2, 3, 4, or 5.

In particular embodiments of formulas 1A and/or 2, the-L³N(L⁴R³)L³-group has one of the following formulas, which may beincorporated in any of formulas 1A to 20 provided herein

In other particular embodiments of Formulas 1A and/or 2, the-L³N(L⁴R³)L³-group has one of the following formulas, which may beincorporated in any of the formulas provided herein

wherein R³¹ and R³² are as defined above, and the carbon in the -L⁴R³moiety that is adjacent to the nitrogen is mono- or di-substituted withdeuterium. In certain examples, the L⁴R³ group is selected from

In some embodiments, disclosed compounds may have a Formula 3 or Formula4, illustrated below.

With reference to either one of Formulas 3 or 4, X, L², Z, L³, ring B,ring A, R², R²², m and n are as provided above. X¹ can be selected fromcarbon, nitrogen, or N-oxide.

In some embodiments, disclosed compounds may have a Formula 5 or Formula6, illustrated below.

With reference to either one of Formulas 5 or 6, X, L², Z, L³, ring B,ring A, R², R²², m and n are as provided above; Z¹ may be selected fromcarbon, oxygen, sulfur, or NR³⁰; and each Y independently is carbon ornitrogen.

In some embodiments, disclosed compounds may have a Formula 7,illustrated below.

With reference to Formula 7, X, L², Z, L³, ring B, ring A, R², R²², mand n are as provided above; X² may be a bond, carbon, oxygen, sulfur,or NR³⁰.

In some embodiments, disclosed compounds may have a Formula 8,illustrated below.

With reference to Formula 8, X, L², Z, L³, ring B, ring A, R², R²², mand n are as provided above; each X³ independently may be nitrogen,carbon, NR³⁰, or oxo; each Y independently may be carbon or NR³⁰.

In yet other embodiments, disclosed compounds may have any one ofFormulas 9-17, illustrated below.

where each X, X¹, X², X³, Z, Z¹, L², L³, L⁴, R², R³, R²², R³⁰, m and nare as previously defined, and Y is carbon or nitrogen for Formulas12-14, and is carbon or NR³⁰ for Formulas 15-17.

In some embodiments, rings A and B are both phenyl, leading to compoundshaving Formula 18:

In certain embodiments, disclosed compounds can have Formula 19,illustrated below.

In certain embodiments of Formulas 18 and 19, L³ is —CHD- or -CD₂-.

In some examples of compounds, rings A and B are six-membered rings, R¹is —OR^(1A) and R² is para to the amide, leading to compounds withFormula 20:

With respect to Formula 20, R^(1A) is hydrogen, aliphatic, or alkyl, R²is halogen, aryl or heteroaryl, R³ is aliphatic, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR^(3A)R^(3B),—C(O)OR^(3A), —S(O)₂NR^(3A)R^(3B), or —C(O)NR^(3A)R^(3B). R^(3A) andR^(3B) are independently hydrogen, aliphatic or alkyl. L¹ is a bond or—NR³⁰—, and L², L³ and L⁴ are independently a bond, alkylene,heteroalkylene, cycloalkylene, heterocycloalkylene or —CR⁹R¹⁰—, and atleast one of L³, L⁴ and R³ comprises at least one deuterium. R⁹ and R¹⁰are independently hydrogen, D, F, aliphatic, alkyl or —C(O)R⁷, whereinR⁷ may be hydrogen, halogen, ═O (oxo), —CF₃, —CN, —CCl₃, —COOH,—CH₂COOH, —OH, —SH, —SO₂Cl, —SO₃H, —SO₂NH₂, —NO₂, —NH₂, —NHNH₂,—NHC(O)NHNH₂, Q, W, Y, and Z are bonded by a single or double bond suchthat the resulting ring is aromatic. Q, W, Y, and Z are independentlyselected from CH, —CR²² or N. R²² is selected from D, F, Cl, aliphaticor alkyl, —CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃. A₁, A₂, A₃, and A₄ arebonded by a single or double bond such that the resulting ring isaromatic. A₁, A₂, A₃, and A₄ are independently selected from —CR²⁷ or N.R²⁷ is selected from H, D, F, Cl, aliphatic or alkyl, —CD₃, —CF₃, —OH,—OCH₃, —OCD₃ or —OCF₃.

R^(1A) may be hydrogen or aliphatic, typically alkyl. In someembodiments, R^(1A) is C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl. In someembodiments, R^(1A) is C₁-C₁₀ aliphatic or alkyl. In some embodiments,R^(1A) is C₂ aliphatic or alkyl.

R³ may be aliphatic, alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl. R³ may be C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl, C₃-C₈(e.g., C₅-C₇) cycloalkyl, 3 to 8-membered (e.g., 3 to 6-membered)heterocycloalkyl, C₅-C₁₀ (e.g., C₅-C₆) aryl, or 5 to 10-membered (e.g.,5 to 6-membered) heteroaryl. In some embodiments, R³ is linear orbranched C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl. In some embodiments,R³ is linear aliphatic or alkyl. In other embodiments, R³ is branchedaliphatic or alkyl. In some embodiments, R³ is C₁-C₅ aliphatic or alkyl.In other embodiments, R³ is C₄ aliphatic or alkyl. In other embodiments,R³ is C₃ aliphatic or alkyl. In some embodiments, R³ is branched C₁-C₅aliphatic or alkyl. In other embodiments, R³ is branched C₄ aliphatic oralkyl. In other embodiments, R³ is branched C₃ aliphatic or alkyl.

R³ may be C₃-C₈ (e.g., C₅-C₇) cycloalkyl. In some embodiments, R³ is 3-to 5-membered (i.e. C₃-C₅) cycloalkyl. In some embodiments, R³ is3-membered (i.e. C₃) cycloalkyl. In some embodiments, R³ is 5-membered(i.e. C₅) cycloalkyl.

In other embodiments, R³ is 3- to 8-membered (e.g., 3- to 6-membered)heterocycloalkyl. In some embodiments, R³ is 5- to 6-memberedheterocycloalkyl. In some embodiments, R³ is 5-memberedheterocycloalkyl. In other embodiments, R³ is 6-memberedheterocycloalkyl.

R³ may be C₅-C₁₀ (e.g., C₅-C₆) aryl or 5- to 10-membered (e.g., 5- to6-membered) heteroaryl. In some embodiments, R³ is 5- to 6-memberedaryl. In some embodiments, R³ is 5-membered aryl. In other embodiments,R³ is 6-membered aryl. Thus, in some embodiments, R³ is phenyl. In someembodiments, R³ is 5- to 6-membered heteroaryl. In some embodiments, R³is 5-membered heteroaryl. In other embodiments, R³ is 6-memberedheteroaryl.

L¹, L², L³ and L⁴ may be the same or different and may eachindependently be a bond, —NR³⁰—, —S(O)—, —S(O)₂NH—, —NHS(O)₂—, —C(O)O—,—OC(O)—C(O)—, —C(O)NH—, —NH—, —NHC(O)—, —O—, —S—, alkylene,heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene, and at least one of L³ and L⁴ comprises at least onedeuterium. In some embodiments, L¹, L², L³ and L⁴ are independently abond, —C(O)O—, —OC(O)—C(O)—, —C(O)NH—, —NH—, —NHC(O)—, —O—, —S—,alkylene, heteroalkylene, cycloalkylene, heterocykloalkylene, arylene,or heteroarylene.

As described above, L², L³ and L⁴ may be independently a bond or C₁-C₂₀(e.g., C₁-C₆) alkylene. In some embodiments, L² is C₁-C₅ alkylene. Inother embodiments, L² is C₅ alkylene. In some embodiments, L² is linearC₅ alkylene. In other embodiments, L² is branched C₅ alkylene.

As described above, L³ and L⁴ may be independently a bond or C₁-C₂₀(e.g., C₁-C₆) alkylene. Thus, in some embodiments, L³ and L⁴ areindependently a bond or C₁-C₅ alkylene. In some embodiments, L³ is abond or C₁-C₅ alkylene. In some embodiments, L³ is methylene. In otherembodiments, L⁴ is a bond or C₁-C₅ alkylene. In some embodiments, L⁴ ismethylene, ethylene or propylene. In some embodiments, L⁴ is methylene.In other embodiments, L⁴ is ethylene. In other embodiments, L⁴ ispropylene.

In some embodiments of Formula 1, L⁵ is

leading to compounds having Formulas 21 and 22 respectively

In some embodiments, of Formulas 21 and 22, R^(c3) is alkyl or CF₃, andin certain embodiments, R^(c3) is methyl. In some examples, p is 0 andin some other examples, p is 1.

Ring C may be a 5-membered heterocyclyl or a 5-membered heteroaryl, andin certain embodiments, ring C is a 5-membered heteroaryl. Ring C may bea nitrogen-containing heteroaryl or heterocyclyl, and in certainexamples, ring C is selected from imidazole, pyrazole, pyrrole,triazole, tetrazole, thiazole, isothiazole, thiadiazole, oxazole,isoxazole, oxadiazole, imidazoline, pyrrolidine, thiazoline oroxazoline. In some embodiments, a point of connection to ring A or apoint of connection to ring B, or both, is through one or more nitrogensin ring C. Exemplary

groups include, but are not limited to,

In certain embodiments of Formulas 21 and 22, the compounds haveformulas selected from

In certain particular embodiments of the any of the Formulas providedabove, R^(1A) is hydrogen, aliphatic, or alkyl. R² is halogen or furan,R³, if present, is aliphatic, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl. L¹ is a bond or —NR³⁰— and L², L³and L⁴, if present, are independently a bond or alkylene, and at leastone of L³, L⁴ and R³, or at least one of R^(c1) and R^(c2), comprises atleast one deuterium.

In some embodiments, the compound has the structure:

In some embodiments, the compound is selected from:

-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid ethyl    6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl-1-d)phenoxy)hexanoate    ethyl    6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl-1-d)phenoxy)hexanoate    ethyl    6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl-1-d)phenoxy)hexanoate-   6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl-1-d)phenoxy)hexanoic    acid-   6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl-1-d)phenoxy)hexanoic    acid-   N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl-1-d)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide-   6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-[1,1′-biphenyl]-4-carboxamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-4-(pyridin-3-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-4-(pyridin-4-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-4-(1H-pyrazol-4-yl)benzamide-   N-benzyl-4-(furan-2-yl)-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)benzamide-   N-benzyl-4-(furan-3-yl)-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-4-(thiophen-2-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d)-4-(thiophen-3-yl)benzamide-   6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((N-(sec-butyl)[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(thiophen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-3-enoic    acid-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-4-enoic    acid-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-3-enoic    acid-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-4-enoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-4-ynoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hex-3-ynoic    acid-   N-((2-((5-(1H-tetrazol-5-yl)pentyl)oxy)phenyl)methyl-d)-N-cyclopropyl-4-(furan-2-yl)benzamide-   6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)thiophen-3-yl)oxy)hexanoic    acid-   6-(2-((N-cyclopropyl-[2,3′-bifuran]-5′-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-5-(furan-2-yl)thiazole-2-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(cyclopropyl((4-(furan-2-yl)phenyl)methyl-d)carbamoyl)phenoxy)hexanoic    acid-   6-(2-(((4-(furan-2-yl)phenyl)methyl-d)(2-morpholinoethyl)carbamoyl)phenoxy)hexanoic    acid-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(6-hydroxy-4-oxo-4H-1,3-dioxin-2-yl)pentyl)oxy)phenyl)methyl-d)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxyisoxazol-5-yl)pentyl)oxy)phenyl)methyl-d)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)pentyl)oxy)phenyl)methyl-d)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxyisothiazol-5-yl)pentyl)oxy)phenyl)methyl-d)benzamide-   N-cyclopropyl-N-((2-((5-(2,4-dioxooxazolidin-5-yl)pentyl)oxy)phenyl)methyl-d)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,4-dioxothiazolidin-5-yl)pentyl)oxy)phenyl)methyl-d)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,5-dioxo-2,5-dihydro-1H-imidazol-4-yl)pentyl)oxy)phenyl)methyl-d)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pentyl)oxy)phenyl)methyl-d)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pentyl)oxy)phenyl)methyl-d2)-4-(furan-2-yl)benzamide-   N-(cyclopropyl-1-d)-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide-   6-(2-((4-chloro-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((N-isopropyl-4-methoxybenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-acetyl-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-methylbenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((4-fluoro-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((N-isopropyl-4-(4-methoxytetrahydro-2H-pyran-4-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((3′-(furan-3-yl)-N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-3-ylethynyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopentylethynyl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(cyclobutylethynyl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-((1-methylazetidin-3-yl)ethynyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1-methoxycyclopropyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1-(trifluoromethyl)cyclopropyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(tetrahydro-2H-pyran-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-methylbicyclo[2.2.2]octan-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(6-oxo-1,6-dihydropyridin-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-2-ylethynyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-phenylbicyclo[2.2.2]octan-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-cyano-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((4-(furan-2-yl)-N-isopropylphenyl)sulfonamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylthiophene-2-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-isopropylthiazole-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(((4-(furan-2-yl)phenyl)methyl-d)(isopropyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl-1-d)phenoxy)hexanoic    acid-   6-(2-((3-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((2-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-N-isopropylpiperidine-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylisoxazole-3-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylcyclohexane-1-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-1H-indazol-3-yl)(isopropyl)amino)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylthiazole-2-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-isopropyloxazole-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-2-methylbenzofuran-6-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-2-methylbenzofuran-5-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropyl-2,5-dioxopiperazine-1-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-N-isopropyl-2-oxopiperidine-4-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((7-(furan-2-yl)-4-oxoquinazolin-3(4H)-yl)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-3,6-dioxopiperazine-2-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylpiperidine-1-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic acid-   6-(2-((4-(furan-2-yl)-N-(oxetan-3-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(2-cyanopropan-2-yl)-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-3-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-hydroxybenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(1-(4-(furan-2-yl)benzoyl)piperidin-2-yl-2-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methoxybenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropylmethyl)-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(1-cyclopropylethyl)-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(1-(4-(furan-2-yl)benzoyl)pyrrolidin-2-yl-2-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)-4-methylphenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(2-(4-(furan-2-yl)phenyl)pyrrolidine-1-carbonyl-2-d)phenoxy)hexanoic    acid-   6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-(2-(4-(furan-2-yl)phenyl)piperidine-1-carbonyl-2-d)phenoxy)hexanoic    acid-   6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)-4-methoxyphenoxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)pyridin-2-yl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)pyridin-3-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)pyridin-4-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)-1-methyl-1H-pyrazol-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)pyridin-3-yl)oxy)hexanoic    acid-   6-((2-(4-(furan-2-yl)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl-1-d)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)isothiazol-3-yl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)cyclopentyl)oxy)hexanoic    acid-   6-(4-cyclopropyl-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)cyclohexyl)oxy)hexanoic    acid-   6-(4-(azetidin-1-yl)-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)-4-(trifluoromethyl)phenoxy)hexanoic    acid-   N-((2-(4-(2H-tetrazol-5-yl)butoxy)phenyl)methyl-d)-4-(furan-2-yl)-N-isopropylbenzamide-   7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)heptanoic    acid-   2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)propoxy)acetic    acid-   5-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethyl)isoxazole-3-carboxylic    acid-   2-(5-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)methyl)isoxazol-3-yl)acetic    acid-   2-(4-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)cyclohexyl)acetic    acid-   5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)pentanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethoxy)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)acetamido)propanoic    acid-   3-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)methyl)thiazol-2-yl)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethyl)cyclobutane-1-carboxylic    acid-   3-((2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethyl)amino)-3-oxopropanoic    acid-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)azetidin-1-yl)propanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)heptanoic    acid-   2-(3-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)methyl)azetidin-1-yl)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)cyclopentyl)oxy)acetic    acid-   2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)methyl)thiazol-2-yl)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)propyl)thio)acetic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethyl)azetidine-3-carboxylic    acid-   2-(4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetic    acid-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)piperidin-1-yl)propanoic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)acetyl)pyrrolidine-3-carboxylic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)ethyl)pyrrolidine-3-carboxylic    acid-   (E)-6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenoxy)-4-methylhex-4-enoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)pyrrolidin-3-yl)oxy)hexanoic    acid-   4-(furan-2-yl)-N-((2-(4-(5-hydroxy-1,3,4-oxadiazol-2-yl)butoxy)phenyl)methyl-d)-N-isopropylbenzamide-   6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)morpholin-3-yl)oxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopropylethynyl)-N-methylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)morpholin-3-yl)oxy)hexanoic    acid-   6-(2-((N-methyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-methylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-methylpicolinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-methylthiazole-2-carboxamido)methyl-d)phenoxy)hexanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)phenoxy)ethoxy)propanoic    acid-   N-((2-(4-(2H-tetrazol-5-yl)butoxy)phenyl)methyl-d)-4-(furan-2-yl)-N-methylbenzamide-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)phenoxy)heptanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)-4-methoxyphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)-4-methylphenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-((3-((6-(furan-2-yl)-N-methylnicotinamido)methyl-d)pyridin-2-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)pyridin-2-yl)oxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-methylnicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-(but-2-yn-1-yl)-6-(furan-2-yl)nicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(furan-2-ylmethyl)nicotinamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-6-fluoronicotinamido)methyl-d)phenoxy)hexanoic acid    sodium    6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d)phenoxy)hexanoate-   6-(2-((4-((difluoromethyl)thio)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-6-fluoronicotinamido)methyl-d)phenoxy)hexanoic acid-   (E)-6-(2-((4-(furan-2-yl)-N′-hydroxy-N-isopropylbenzimidamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-fluoro-5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-((fluoromethyl)thio)-N-isopropylbenzamido)methyl-d)phenoxy)hexanoic    acid-   (6R)-6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d)phenoxy)heptanoic    acid-   6-(2-((5-(cyclopropylethynyl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d)phenoxy)hexanoic    acid-   (2S)-4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d)phenyl)sulfonyl)-2,3-dihydro-1H-indene-2-carboxylic    acid-   6-(2-(((4-(furan-2-yl)phenyl)methyl-d)(isopropyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl-1-d)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid ethyl    6-(2-(1-(4-bromo-N-(cyclopropyl-1-d)benzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate    ethyl    6-(2-(2-(tert-butylamino)-1-(N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate    ethyl    6-(2-(2-amino-1-(N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate-   6-(2-(2-(tert-butylamino)-1-(N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid-   6-(2-(2-amino-1-(N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid-   N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamide-   6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(phenylmethyl-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(phenylmethyl-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(phenylmethyl-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(phenylmethyl-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(phenylmethyl-d2)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-[1,1′-biphenyl]-4-carboxamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-[1,1′-biphenyl]-4-carboxamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-[1,1′-biphenyl]-4-carboxamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-4-(pyridin-3-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-4-(pyridin-3-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-4-(pyridin-3-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-4-(pyridin-4-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-4-(pyridin-4-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-4-(pyridin-4-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-4-(1H-pyrazol-4-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-4-(1H-pyrazol-4-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-4-(1H-pyrazol-4-yl)benzamide-   N-benzyl-4-(furan-2-yl)-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)benzamide-   4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)benzamide-   4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)benzamide-   N-benzyl-4-(furan-3-yl)-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)benzamide-   4-(furan-3-yl)-N-(2-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)benzamide-   4-(furan-3-yl)-N-(2-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-4-(thiophen-2-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-4-(thiophen-2-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-4-(thiophen-2-yl)benzamide-   N-benzyl-N-((2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)methyl-d2)-4-(thiophen-3-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d)-4-(thiophen-3-yl)benzamide-   N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-N-(phenylmethyl-d2)-4-(thiophen-3-yl)benzamide-   6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-bromo-N-(butan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(butan-2-yl-2-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(3-morpholinopropyl-1,1-d2)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1,1-d2)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1,1-d2)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1,1-d2)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1,1-d2)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(2-(pyridin-2-yl)ethyl-1,1-d2)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-3-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(thiophen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopentyl-1-d)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(naphthalen-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(naphthalen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4′-butyl-N-(cyclopropyl-1-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-3-enoic    acid-   (E)-6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-4-enoic    acid-   (Z)-6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-3-enoic    acid-   (Z)-6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-4-enoic    acid-   (E)-6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-4-ynoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-ynoic    acid-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hex-3-ynoic    acid-   6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-ynoic    acid-   N-((2-((5-(1H-tetrazol-5-yl)pentyl)oxy)phenyl)methyl-d2)-N-cyclopropyl-4-(furan-2-yl)benzamide-   N-(2-((5-(1H-tetrazol-5-yl)pentyl)oxy)benzyl)-N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamide-   6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)thiophen-3-yl)oxy)hexanoic    acid-   6-((4-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)thiophen-3-yl)oxy)hexanoic    acid-   6-(2-((N-cyclopropyl-[2,3′-bifuran]-5′-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-[2,3′-bifuran]-5′-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-5-(furan-2-yl)thiazole-2-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-5-(furan-2-yl)thiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)benzo[c][1,2,5]oxadiazole-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropyl-1-d)-2-oxoindoline-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-(cyclopropyl((4-(furan-2-yl)phenyl)methyl-d2)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((cyclopropyl-1-d)(4-(furan-2-yl)benzyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)phenyl)methyl-d2)(2-morpholinoethyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzyl)(2-morpholinoethyl-1-d)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzyl)(2-morpholinoethyl-1,1-d2)carbamoyl)phenoxy)hexanoic    acid-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(6-hydroxy-4-oxo-4H-1,3-dioxin-2-yl)pentyl)oxy)phenyl)methyl-d2)benzamide-   N-(cyclopropyl-1-d)-4-(furan-2-yl)-N-(2-((5-(6-hydroxy-4-oxo-4H-1,3-dioxin-2-yl)pentyl)oxy)benzyl)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxyisoxazol-5-yl)pentyl)oxy)phenyl)methyl-d2)benzamide-   N-(cyclopropyl-1-d)-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisoxazol-5-yl)pentyl)oxy)benzyl)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)pentyl)oxy)phenyl)methyl-d2)benzamide-   N-(cyclopropyl-1-d)-4-(furan-2-yl)-N-(2-((5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)pentyl)oxy)benzyl)benzamide-   N-cyclopropyl-4-(furan-2-yl)-N-((2-((5-(3-hydroxyisothiazol-5-yl)pentyl)oxy)phenyl)methyl-d2)benzamide-   N-(cyclopropyl-1-d)-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisothiazol-5-yl)pentyl)oxy)benzyl)benzamide-   N-cyclopropyl-N-((2-((5-(2,4-dioxooxazolidin-5-yl)pentyl)oxy)phenyl)methyl-d2)-4-(furan-2-yl)benzamide-   N-(cyclopropyl-1-d)-N-(2-((5-(2,4-dioxooxazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,4-dioxothiazolidin-5-yl)pentyl)oxy)phenyl)methyl-d2)-4-(furan-2-yl)benzamide-   N-(cyclopropyl-1-d)-N-(2-((5-(2,4-dioxothiazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide-   N-cyclopropyl-N-((2-((5-(2,5-dioxo-2,5-dihydro-1H-imidazol-4-yl)pentyl)oxy)phenyl)methyl-d2)-4-(furan-2-yl)benzamide-   N-(cyclopropyl-1-d)-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-imidazol-4-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide-   6-(2-((4-chloro-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-chloro-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-methoxybenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-methoxy-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(dimethylamino)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-acetyl-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-acetyl-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(methylsulfonyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-methylbenzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-methyl-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-fluoro-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-fluoro-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-methoxytetrahydro-2H-pyran-4-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(4-methoxytetrahydro-2H-pyran-4-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((3′-(furan-3-yl)-N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((3′-(furan-3-yl)-N-(propan-2-yl-2-d)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-3-ylethynyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(oxetan-3-ylethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopentylethynyl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopentylethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(cyclobutylethynyl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(cyclobutylethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-((1-methylazetidin-3-yl)ethynyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-((1-methylazetidin-3-yl)ethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1-methoxycyclopropyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(1-methoxycyclopropyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(1-(trifluoromethyl)cyclopropyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(1-(trifluoromethyl)cyclopropyl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(tetrahydro-2H-pyran-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(tetrahydro-2H-pyran-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-methylbicyclo[2.2.2]octan-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(4-methylbicyclo[2.2.2]octan-1-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(oxetan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(6-oxo-1,6-dihydropyridin-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(6-oxo-1,6-dihydropyridin-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(oxetan-2-ylethynyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(oxetan-2-ylethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(propan-2-yl-2-d)-4-(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-4-(4-phenylbicyclo[2.2.2]octan-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(4-phenylbicyclo[2.2.2]octan-1-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-cyano-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-cyano-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylphenyl)sulfonamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)phenyl)sulfonamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)picolinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylthiophene-2-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)thiophene-2-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-isopropylthiazole-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-(propan-2-yl-2-d)thiazole-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-(((4-(furan-2-yl)phenyl)methyl-d2)(isopropyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzyl)(propan-2-yl-2-d)carbamoyl)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl-1,1-d2)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(propan-2-yl-2-d)amino)-2-oxoethyl)phenoxy)hexanoic    acid-   6-(2-((3-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((3-fluoro-4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((2-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-fluoro-4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-N-isopropylpiperidine-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-N-(propan-2-yl-2-d)piperidine-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylisoxazole-3-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)isoxazole-3-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylcyclohexane-1-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)cyclohexane-1-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-1H-indazol-3-yl)(isopropyl)amino)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-1H-indazol-3-yl)(propan-2-yl-2-d)amino)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropylthiazole-2-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)thiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-isopropyloxazole-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-(furan-2-yl)-N-(propan-2-yl-2-d)oxazole-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-2-methylbenzofuran-6-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-methyl-N-(propan-2-yl-2-d)benzofuran-6-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-2-methylbenzofuran-5-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-methyl-N-(propan-2-yl-2-d)benzofuran-5-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropyl-2,5-dioxopiperazine-1-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-(furan-2-yl)-2,5-dioxo-N-(propan-2-yl-2-d)piperazine-1-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-N-isopropyl-2-oxopiperidine-4-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((1-(furan-2-yl)-2-oxo-N-(propan-2-yl-2-d)piperidine-4-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((7-(furan-2-yl)-4-oxoquinazolin-3(4H)-yl)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-3,6-dioxopiperazine-2-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-3,6-dioxo-N-(propan-2-yl-2-d)piperazine-2-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylpiperidine-1-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)piperidine-1-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-1-methyl-N-(propan-2-yl-2-d)-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl-1-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl-1,1-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((4-(furan-2-yl)-N-(oxetan-3-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(2-cyanopropan-2-yl)-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-(furan-2-yl)-3-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-hydroxybenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methoxybenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropylmethyl)-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropylmethyl-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(cyclopropylmethyl-d2)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(1-cyclopropylethyl)-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(1-cyclopropylethyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)-4-methylphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)-4-methylphenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-bromo-2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-cyano-2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)-4-methoxyphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)-4-methoxyphenoxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)pyridin-2-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)pyridin-2-yl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)pyridin-3-yl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)pyridin-3-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)pyridin-4-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)pyridin-4-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)-1-methyl-1H-pyrazol-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)-1-methyl-1H-pyrazol-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)pyridin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)pyridin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)isothiazol-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)isothiazol-3-yl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)cyclopentyl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)cyclopentyl)oxy)hexanoic    acid-   6-(4-cyclopropyl-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-cyclopropyl-2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)cyclohexyl)oxy)hexanoic    acid-   6-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)cyclohexyl)oxy)hexanoic    acid-   6-(4-(azetidin-1-yl)-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-(azetidin-1-yl)-2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)-4-(trifluoromethyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)-4-(trifluoromethyl)phenoxy)hexanoic    acid-   N-((2-(4-(2H-tetrazol-5-yl)butoxy)phenyl)methyl-d2)-4-(furan-2-yl)-N-isopropylbenzamide-   N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamide-   7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)heptanoic    acid-   7-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)heptanoic    acid-   2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)propoxy)acetic    acid-   2-(3-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)propoxy)acetic    acid-   5-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethyl)isoxazole-3-carboxylic    acid-   5-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethyl)isoxazole-3-carboxylic    acid-   2-(5-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)methyl)isoxazol-3-yl)acetic    acid-   2-(5-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)methyl)isoxazol-3-yl)acetic    acid-   2-(4-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)cyclohexyl)acetic    acid-   2-(4-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)cyclohexyl)acetic    acid-   5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)pentanoic    acid-   5-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)pentanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethoxy)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethoxy)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)acetamido)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)acetamido)propanoic    acid-   3-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)methyl)thiazol-2-yl)propanoic    acid-   3-(4-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)methyl)thiazol-2-yl)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethyl)cyclobutane-1-carboxylic    acid-   3-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethyl)cyclobutane-1-carboxylic    acid-   3-((2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethyl)amino)-3-oxopropanoic    acid-   3-((2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethyl)amino)-3-oxopropanoic    acid-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)azetidin-1-yl)propanoic    acid-   3-(3-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)azetidin-1-yl)propanoic    acid-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)heptanoic    acid-   6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)heptanoic    acid-   2-(3-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)methyl)azetidin-1-yl)acetic    acid-   2-(3-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)methyl)azetidin-1-yl)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)cyclopentyl)oxy)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)cyclopentyl)oxy)acetic    acid-   2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)methyl)thiazol-2-yl)acetic    acid-   2-(4-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)methyl)thiazol-2-yl)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)propyl)thio)acetic    acid-   2-((3-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)propyl)thio)acetic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethyl)azetidine-3-carboxylic    acid-   1-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethyl)azetidine-3-carboxylic    acid-   2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetic    acid-   2-(4-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetic    acid-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)piperidin-1-yl)propanoic    acid-   3-(3-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)piperidin-1-yl)propanoic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)acetyl)pyrrolidine-3-carboxylic    acid-   1-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)acetyl)pyrrolidine-3-carboxylic    acid-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)ethyl)pyrrolidine-3-carboxylic    acid-   1-(2-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)ethyl)pyrrolidine-3-carboxylic    acid-   (E)-6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenoxy)-4-methylhex-4-enoic    acid-   (E)-6-(2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)-4-methylhex-4-enoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)pyrrolidin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)pyrrolidin-3-yl)oxy)hexanoic    acid-   4-(furan-2-yl)-N-((2-(4-(5-hydroxy-1,3,4-oxadiazol-2-yl)butoxy)phenyl)methyl-d2)-N-isopropylbenzamide-   4-(furan-2-yl)-N-(2-(4-(5-hydroxy-1,3,4-oxadiazol-2-yl)butoxy)benzyl)-N-(propan-2-yl-2-d)benzamide-   6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopropylethynyl)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)morpholin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)morpholin-3-yl)oxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(phenylmethyl-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(phenylmethyl-d2)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopropylethynyl)-N-methylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-(cyclopropylethynyl)-N-(methyl-d3)benzamido)methyl)phenoxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)morpholin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)morpholin-3-yl)oxy)hexanoic    acid-   6-(2-((N-methyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(methyl-d3)-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-methylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-cyclopropoxy-N-(methyl-d3)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-methylpicolinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(methyl-d3)picolinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-methylthiazole-2-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(furan-2-yl)-N-(methyl-d3)thiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)phenoxy)ethoxy)propanoic    acid-   3-(2-(2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)phenoxy)ethoxy)propanoic    acid-   N-((2-(4-(2H-tetrazol-5-yl)butoxy)phenyl)methyl-d2)-4-(furan-2-yl)-N-methylbenzamide-   N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-(methyl-d3)benzamide-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)phenoxy)heptanoic    acid-   6-(2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)phenoxy)heptanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)-4-methoxyphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)-4-methoxyphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)-4-methylphenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)-4-methylphenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(4-fluoro-2-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)phenoxy)hexanoic    acid-   6-((3-((6-(furan-2-yl)-N-methylnicotinamido)methyl-d2)pyridin-2-yl)oxy)hexanoic    acid-   6-((3-((6-(furan-2-yl)-N-(methyl-d3)nicotinamido)methyl)pyridin-2-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)pyridin-2-yl)oxy)hexanoic    acid-   6-((3-((4-(furan-2-yl)-N-(methyl-d3)benzamido)methyl)pyridin-2-yl)oxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-isopropylnicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-methylnicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-(cyclopropylethynyl)-N-(methyl-d3)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(but-2-yn-1-yl)-6-(furan-2-yl)nicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((N-(but-2-yn-1-yl-1-d)-6-(furan-2-yl)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-(but-2-yn-1-yl-1,1-d2)-6-(furan-2-yl)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-isopropylnicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(furan-2-ylmethyl)nicotinamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(furan-2-ylmethyl-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(furan-2-ylmethyl-d2)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-6-fluoronicotinamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((6-fluoro-N-(phenylmethyl-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(phenylmethyl-d2)nicotinamido)methyl)phenoxy)hexanoic    acid sodium    6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl-d2)phenoxy)hexanoate    sodium    6-(2-((N-(cyclopropyl-1-d)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate-   6-(2-((4-((difluoromethyl)thio)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-((difluoromethyl)thio)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-6-fluoronicotinamido)methyl-d2)phenoxy)hexanoic acid-   6-(2-((6-fluoro-N-(phenylmethyl-d)nicotinamido)methyl)phenoxy)hexanoic    acid-   6-(2-((6-fluoro-N-(phenylmethyl-d2)nicotinamido)methyl)phenoxy)hexanoic    acid-   (E)-6-(2-((4-(furan-2-yl)-N′-hydroxy-N-isopropylbenzimidamido)methyl-d2)phenoxy)hexanoic    acid-   (E)-6-(2-((4-(furan-2-yl)-N′-hydroxy-N-(propan-2-yl-2-d)benzimidamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-fluoro-5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-fluoro-5-(furan-2-yl)-N-(propan-2-yl-2-d)-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-((fluoromethyl)thio)-N-isopropylbenzamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((4-((fluoromethyl)thio)-N-(propan-2-yl-2-d)benzamido)methyl)phenoxy)hexanoic    acid-   (R)-6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d2)phenoxy)heptanoic    acid-   (R)-6-(2-((5-(furan-2-yl)-N-(propan-2-yl-2-d)-1H-pyrazole-3-carboxamido)methyl)phenoxy)heptanoic    acid-   6-(2-((5-(cyclopropylethynyl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((5-(cyclopropylethynyl)-N-(propan-2-yl-2-d)-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid-   (S)-4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl-d2)phenyl)sulfonyl)-2,3-dihydro-1H-indene-2-carboxylic    acid-   (S)-4-((2-((4-(furan-2-yl)-N-(propan-2-yl-2-d)benzamido)methyl)phenyl)sulfonyl)-2,3-dihydro-1H-indene-2-carboxylic    acid-   6-(2-(((4-(furan-2-yl)phenyl)methyl-d2)(isopropyl)carbamoyl)phenoxy)hexanoic    acid-   6-(2-((4-(furan-2-yl)benzyl)(propan-2-yl-2-d)carbamoyl)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl-1,1-d2)phenoxy)hexanoic    acid-   6-(2-(2-((4-(furan-2-yl)phenyl)(propan-2-yl-2-d)amino)-2-oxoethyl)phenoxy)hexanoic    acid-   (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d)phenoxy)-4-methylhex-4-enoic    acid-   (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl-d2)phenoxy)-4-methylhex-4-enoic    acid-   6-(2-((4-(4-(furan-2-yl)phenyl)-2-methylthiazol-5-yl)methyl-d)phenoxy)hexanoic    acid-   6-(2-((4-(4-(furan-2-yl)phenyl)-2-methylthiazol-5-yl)methyl-d2)phenoxy)hexanoic    acid-   6-(2-((2-([1,1′-biphenyl]-4-yl)-5-methyl-1H-imidazol-1-yl)methyl-d)phenoxy)hexanoic    acid-   6-(2-((2-([1,1′-biphenyl]-4-yl)-5-methyl-1H-imidazol-1-yl)methyl-d2)phenoxy)hexanoic    acid-   (E)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl-d)phenoxy)-4-methylhex-4-enoic    acid-   (E)-6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl-d2)phenoxy)-4-methylhex-4-enoic    acid-   6-(2-((5-methyl-2-(2-methylbenzofuran-5-yl)-1H-imidazol-1-yl)methyl-d)phenoxy)hexanoic    acid-   6-(2-((5-methyl-2-(2-methylbenzofuran-5-yl)-1H-imidazol-1-yl)methyl-d2)phenoxy)hexanoic    acid

III. Method of Making the Compounds

Disclosed compounds can be prepared to the carboxylic acid or hydroxamicacid at L¹ respectively, as exemplified below and as will be understoodby a person of ordinary skill in the art of organic synthesis. For thepreparation of the corresponding salts, an additional step would beperformed. An exemplary synthesis may include the following 1″ reactionstep:

An alkylation reaction, specifically an etherification reaction, isperformed where a hydroxyaryl or hydroxyheteroaryl moiety is reactedwith an alkylating agent. For the hydroxyaryl or hydroxyheteroarylmoiety, the ring atoms are CR^(A) or N; and R^(A) is selected from H, D,F, Cl, lower aliphatic or alkyl, —CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃.A suitable exemplary alkylating agent is an alkyl bromideR₁—O-L¹(CO)L²-Br. The reactants are combined in the presence of a molarexcess of a carbonate base (e.g. M=Na, K or Cs). The reaction is carriedout in a polar aprotic solvent with a boiling point >100° C. such asDMF, DMA or DME. Typical reaction concentrations are 0.1 to 1.0M.Reactants are heated to >100° C., under ambient or elevated pressure,such as with microwave assisted organic synthesis (MAOS), for a periodof time ranging from minutes to hours until both reactants are consumed.Exemplary aldehydes include:

Exemplary linkers include:

where m and n independently are selected from a range of 1-6 and R¹(referred to herein as R^(1A)) is aliphatic, typically alkyl. Generallythe distance between the bromide and the carbonyl carbon is 4-8carbon-carbon bond lengths. Isolation, purification and characterizationof the product aldehyde would be consistent with that typicallypracticed by one of ordinary skill in the art.

An exemplary 2^(nd) step of the reaction process is provided below:

The 2^(nd) reaction step is generally characterized as a reductiveamination reaction of an aldehyde and primary amine, such as R³-L⁴-NH₂,where the reducing nucleophile is L³. L³ can be —H, -D, —CH₃, aliphatic,typically alkyl, and more typically lower alkyl. In certain embodiments,the L³ reducing agent is a deuterated reducing agent such as, but notlimited to, diborane-d6, sodium borodeuteride, sodium cyanoborodeuterideand deuterium. The reaction conditions are performed so thatmonoalkylation is the major product and over alkylation to the tertiaryamine is suppressed. Reducing agents and co-solvent reaction additivesare numerous, but readily known to those of ordinary skill in the art.Some exemplary primary amines comprising R³ and L⁴ functionalitiesinclude:

Solvents typically are chlorinated hydrocarbons, such as CH₂Cl₂, CHCl₃,or 1,2-dichloroethane. Reaction temperature and reaction time varydepending on the reaction temperature selected. As described above, MAOSversions of reductive amination exist.

The 3^(rd) reaction step is generally characterized as a secondary amineacylation reaction. Exemplary acylating reagents include 4-bromobenzoylor 4-bromoheteroaryoyl compounds. X typically is a leaving group, suchas F, Cl, OTf, or similar favorable leaving group.

A₁, A₂, A₃, and A₄ are bonded by a single or double bond such that theresulting ring is aromatic; A₁, A₂, A₃, and A₄ are independentlyselected from —CR¹² or N; R¹² is selected from H, D, F, Cl, lower alkyl,—CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃. Representative examples include:

Typical reagent conditions include using a base, typically anon-nucleophillic base, or a hindered base having attenuatednucleophilicity, in excess molar amounts. Hindered amine bases, such asHunig's base (N,N-diisopropylethylamine), would be a suitable choice, aswill be recognized by a person of ordinary skill in the art. Solventstypically are chlorinated hydrocarbons, such as CH₂Cl₂, CHCl₃, or1,2-dichloroethane. Reaction temperature and reaction time varydepending on the reaction temperature selected. As described above, MAOSversions of secondary amine acylation exist.

The 4^(th) reaction step is generally characterized as a biaryl,aryl-heteroaryl or heteroaryl-heteroaryl coupling reaction mediatedcatalytically by a transition metal or transition metal complex.

Numerous coupling reactions are known to those of ordinary skill in theart. In this embodiment, the coupling reaction could be theSuzuki-Miyaura cross-coupling where X is boronate —B(OH)₂, M ispalladium, L is triphenylphosphine (PPh₃), and n is 4. With Pd(PPh₃)₄ asthe catalyst, the cross-coupling reaction would be carried out in thepresence of a base, such as a Na, K or Cs carbonate, in a ternarysolvent system of DME, EtOH and Water. R² may be any aryl, aryl,heteroaryl, heteroaryl boronic acid, boronate ester or potassiumtrifluroboronate salt in this cross-coupling example. Exemplary R²moieties include:

Reaction temperature and reaction time vary depending on the reactiontemperature selected. As described above, MAOS versions ofcross-coupling reactions exist.

The final step of this exemplary reaction sequence is saponification ofR¹ where L¹ is a bond, thereby converting the carboxylic ester to thecarboxylic acid. Where L¹ is nitrogen, R¹ is deprotected to thehydroxamic acid according to methods known to those of ordinary in theart. This reaction step is as follows:

Typically the base is a hydroxide salt, such as Li, Na, K or Cshydroxide. Suitable solvents include, but are not limited to, water,THF, alcohols, such as methanol, ethanol, propanol or isopropanol, DMF,DMSO, or any combination thereof. Reaction temperature and reaction timevary depending on the reaction temperature selected. As described above,MAOS versions of saponification reactions exist.

Additional formulation of these compounds include converting thecarboxylic acid or hydroxamic acid versions to their complimentarypharmaceutically relevant salts. The various methods for salt formationare known to a person of ordinary skill in the art. An exemplary schemeis provided below.

IV. Pharmaceutical Compositions and Administration

A. Additional Therapeutic Agents

Pharmaceutical compositions are disclosed that include one or morecompounds provided herein (such as 1, 2, 3, 4 or 5 of such compounds),and typically at least one additional substance, such as an excipient, aknown therapeutic other than those of the present disclosure, andcombinations thereof. In some embodiments, the disclosed PPAR agonistscan be used in combination with other agents known to have beneficial,additive or synergistic activity with the disclosed PPAR agonists. Forexample, disclosed compounds can be administered alone or in combinationwith: one or more other PPAR agonists, such as a thiazolidinedione,including rosiglitazone, pioglitazone, troglitazone, and combinationsthereof, or a sulfonylurea agent or a pharmaceutically acceptable saltthereof, such as tolbutamide, tolazamide, glipizide, carbutamide,glisoxepide, glisentide, glibornuride, glibenclamide, gliquidoneglimepiride, gliclazide and the pharmaceutically acceptable salts ofthese compounds, or muraglitazar, farglitazar, naveglitazar,netoglitazone, rivoglitazone, K-111, GW-677954, (−)-Halofenate, acid,arachidonic acid, clofbrate, gemfibrozil, fenofibrate, ciprofibrate,bezafibrate, lovastatin, pravastatin, simvastatin, mevastatin,fluvastatin, indomethacin, fenoprofen, ibuprofen, and thepharmaceutically acceptable salts of these compounds; furtherpharmacologically active substances which having favorable effects onmetabolic disturbances or disorders frequently associated therewith,such as RXR agonists for treating metabolic and cardiovascular diseasesmedicaments, which lower blood glucose; antidiabetics, such as insulinsand insulin derivatives, including Lantus, Apidra, and other fast-actinginsulins, and GLP-1 receptor modulators; active ingredients for treatingdyslipidemias; anti-atherosclerotic medicaments; anti-obesity agents;anti-inflammatory active ingredients; active ingredients for treatingmalignant tumors; anti-thrombotic active ingredients; active ingredientsfor treating high blood pressure; active ingredients for treating heartfailure, and combinations thereof.

Where cancer is being treated, one or more disclosed PPAR agonists canbe used in combination with other agents for treating liquid, solidand/or metastatic tumors. Exemplary chemotherapeutic agents includeagents that interfere with DNA replication, mitosis and chromosomalsegregation, agents that disrupt the synthesis and fidelity ofpolynucleotide precursors, alkylating agents, antimetabolites, cytotoxicantibiotics, vinca alkaloids, tyrosine kinase inhibitors,metalloproteinase and COX-2 inhibitors, cyclophosphamide, cisplatin,docetaxel, paclitaxel, erlotinib, irinotecan, gemcitabine and cisplatin.Other particular examples of chemotherapeutic agents that can be used incombination with the disclosed compounds include alkylating agents, suchas nitrogen mustards (for example, chlorambucil, chlormethine,cyclophosphamide, ifosfamide, and melphalan), nitrosoureas (for example,carmustine, fotemustine, lomustine, and streptozocin), platinumcompounds (for example, carboplatin, cisplatin, oxaliplatin, andBBR3464), busulfan, dacarbazine, mechlorethamine, procarbazine,temozolomide, thiotepa, and uramustine; folic acid (for example,methotrexate, pemetrexed, and raltitrexed), purine (for example,cladribine, clofarabine, fludarabine, mercaptopurine, and tioguanine),pyrimidine (for example, capecitabine), cytarabine, fluorouracil, andgemcitabine; plant alkaloids, such as podophyllum (for example,etoposide, and teniposide); microtubule binding agents (such aspaclitaxel, docetaxel, vinblastine, vindesine, vinorelbine (navelbine)vincristine, the epothilones, colchicine, dolastatin 15, nocodazole,podophyllotoxin, rhizoxin, and derivatives and analogs thereof), DNAintercalators or cross-linkers (such as cisplatin, carboplatin,oxaliplatin, mitomycins, such as mitomycin C, bleomycin, chlorambucil,cyclophosphamide, and derivatives and analogs thereof), DNA synthesisinhibitors (such as methotrexate, 5-fluoro-5′-deoxyuridine,5-fluorouracil and analogs thereof); anthracycline family members (forexample, daunorubicin, doxorubicin, epirubicin, idarubicin,mitoxantrone, and valrubicin); antimetabolites, such ascytotoxic/antitumor antibiotics, bleomycin, rifampicin, hydroxyurea, andmitomycin; topoisomerase inhibitors, such as topotecan and irinotecan;photosensitizers, such as aminolevulinic acid, methyl aminolevulinate,porfimer sodium, and verteporfin, enzymes, enzyme inhibitors (such ascamptothecin, etoposide, formestane, trichostatin and derivatives andanalogs thereof), kinase inhibitors (such as imatinib, gefitinib, anderolitinib), gene regulators (such as raloxifene, 5-azacytidine,5-aza-2′-deoxycytidine, tamoxifen, 4-hydroxytamoxifen, mifepristone andderivatives and analogs thereof); and other agents, such asalitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide,asparaginase, axitinib, bexarotene, bevacizumab, bortezomib, celecoxib,denileukin diftitox, estramustine, hydroxycarbamide, lapatinib,pazopanib, pentostatin, masoprocol, mitotane, pegaspargase, tamoxifen,sorafenib, sunitinib, vemurafinib, vandetanib, and tretinoin. In oneexample, the disclosed compounds are used in combination with a biologicfor treating cancer (e.g., an antibody, such as a humanized antibody,which can be polyclonal, monoclonal, or chimeric, for examplealemtuzumab, bevacizumab, cetuximab, gemtuzumab, rituximab, panitumumab,pertuzumab, or trastuzumab).

Orally effective hypoglycemic active ingredients that can be used incombination with one or more of the disclosed compounds include, forexample, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, DPP-IV inhibitors, potassium channel openers, insulinsensitizers, inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism and lead to a change in the bloodlipid composition, compounds which reduce food intake, and activeingredients which act on the ATP-dependent potassium channel of the betacells.

In certain embodiments, disclosed compounds are administered incombination with substances which influence hepatic glucose productionsuch as, for example, glycogen phosphorylase inhibitors; administered incombination with a biguanide such as, for example, metformin;administered in combination with a DPPIV inhibitor, such as(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate); administered in combination with an α-glucosidaseinhibitor such as, for example, miglitol or acarbose; administered incombination with a bile acid reabsorption inhibitor; administered incombination with a polymeric bile acid adsorbent, such as, for example,cholestyramine or colesevelam; administered in combination with acholesterol absorption inhibitor, such as ezetimibe, tiqueside, orpamaqueside; administered in combination with an LDL receptor inducer;administered in combination with a mixed PPAR alpha/gamma agonist suchas, for example, Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), or(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)et-hoxy]phenyl]methyl]glycine);administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate; administered incombination with nicotinic acid or niacin; administered in combinationwith a CETP inhibitor, such as torcetrapib; administered in combinationwith an ACAT inhibitor; administered in combination with an MTPinhibitor such as, for example, implitapide; administered in combinationwith an antioxidant; administered in combination with a lipoproteinlipase inhibitor; administered in combination with an ATP citrate lyaseinhibitor; administered in combination with a squalene synthetaseinhibitor; administered in combination with fenfluramine ordexfenfluramine; administered in combination with sibutramine;administered in combination with leptin.

In one embodiment, disclosed compounds may be administered incombination with dexamphetamine, amphetamine, mazindole or phentermine;and administered in combination with medicaments having ananti-inflammatory effect.

B. Excipients and Dosage Forms

The present disclosure provides pharmaceutical compositions that includea prophylactically or therapeutically effective amount of one or moredisclosed compounds (such as 1, 2, 3, 4 or 5 disclosed compounds) inadmixture with at least one pharmaceutically acceptable material, suchas an excipient. Disclosed pharmaceutical compositions include adetectable amount of the PPAR agonist, such as greater than 0% to lessthan 100%, such as from 5% to 99%, or from about 50% to about 99%, orfrom 25% to about 99% by weight of the PPAR agonist of the presentdisclosure.

Disclosed compositions can be administered in any suitable dosage form,such as tablets, pills, capsules, powders, granules, sterile solutionsor suspensions, metered aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories. The compositions are intendedfor any suitable administration route, including oral, parenteral,intranasal, sublingual, rectal, transdermal, inhalation or insufflation.The compositions may be formulated by methods known by those of ordinaryskill in the art, such as described in Remington's PharmaceuticalSciences (15th ed., Mack Publishing Company, Easton, Pa., 1980).

The compositions can be administered for therapeutic or prophylactictreatments. In therapeutic applications, compositions are administeredto a subject suffering from a disease (e.g., a PPARδ related disease) ina “therapeutically effective dose.” Amounts effective for this use candepend upon the severity of the disease and the general state of thesubject's health. Single or multiple administrations of the compositionscan be administered depending on the dosage and frequency as requiredand tolerated by the subject. Also, the composition, shape, and type ofdosage forms may vary depending on their use. For example, a dosage formused for acute treatment of a disease or disorder may contain largeramounts of the active ingredient than a dosage form used in the chronictreatment of the same disease or disorder. Similarly, a parenteraldosage form may contain smaller amounts of the active ingredient than anoral dosage form.

Oral dosage forms include, but are not limited to, tablets (includingwithout limitation scored or coated tablets), pills, granules, lozenges,caplets, capsules, chewable tablets, powder packets, cachets, troches,wafers, aerosol sprays, mucosal patches, or liquids, such as syrups,elixirs, solutions or suspensions in an aqueous liquid, for examplewater or saline, a non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil emulsion. Typical oral dosage forms may be prepared bycombining the pharmaceutically acceptable PPAR agonist, potentially in aliquid, solid, granule or gelatin for and/or in a salt form, inadmixture with at least one excipient including, but are not limited to,surface stabilizers, dispersion aids, binders, filling agents,lubricating agents, glidants, suspending agents, sweeteners, flavoringagents, preservatives, buffers, wetting agents, disintegrants,effervescent agents, humectants, controlled release agents, absorptionaccelerators, absorbents, plasticizers, lactose, sucrose, mannitol,sorbitol, calcium phosphates, corn starch, potato starch, cellulose,hydroxy propyl methyl cellulose, microcrystalline cellulose, gelatin,acacia, sodium alginate, alginic acid, tragacanth, guar gum, gelatin,colloidal silicon dioxide, talc, magnesium stearate, stearic acid,colorants, diluents, talc, calcium carbonate, kaslin, maltodextrin,polymethacrylates, moistening agents, preservatives, dyes, and anycombination thereof.

Disintegrants facilitate producing tablets that disintegrate whenexposed to an aqueous environment. The amount of disintegrant usedvaries based upon the type of formulation and mode of administration,and is readily determined by a person of ordinary skill in the art.Typical pharmaceutical compositions comprise from about 0.5 to about 15weight percent of disintegrant, such as from about 1 to about 5 weightpercent of disintegrant. Disintegrants include, but are not limited to,agar-agar, alginic acid, guar gum, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, carboxymethylcellulose calcium,methylcellulose, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, clays, other algins, other celluloses, gums, and mixturesthereof.

Exemplary lubricants include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), sodium benzoate, sodium stearylfumarate, zinc stearate,ethyl oleate, ethyl laureate, agar, syloid silica gel, synthetic silica,and mixtures thereof. Lubricants typically are used in an amount of lessthan about 1 weight percent of the pharmaceutical compositions.

Disclosed PPAR agonists, and related forms, such as salts, can beadministered as controlled- or delayed-release formulations.Controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledrelease counterparts. These dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,alginic acid, aliphatic polyesters, bentonite, cellulose acetate,phthalate, carnuba wax, chitosan, ethylcellulose, guar gum,microcrystalline wax, paraffin, polymethacrylates, povidone, xanthangum, yellow wax, carbomers, hydroxypropylcellulose, andhydroxypropylmethylcellulose.

Pharmaceutical compositions can also include large, slowly metabolizedmacromolecules such as proteins, polysaccharides, such as chitosan,polylactic acids, polyglycolic acids and copolymers (such as latexfunctionalized Sepharose™, agarose, cellulose, and the like), polymericamino acids, amino acid copolymers, and lipid aggregates (such as oildroplets or liposomes). Additionally, these carriers can function asimmunostimulating agents (i.e., adjuvants).

The compositions provided herein, alone or in combination with othersuitable components, can be made into aerosol formulations (e.g., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Suitable formulations for rectal administration include, for example,suppositories. Exemplary suppositories include a suppository base, suchas natural or synthetic triglycerides or paraffin hydrocarbons. Gelatinrectal capsules include a combination of the compound of choice with abase, including, for example, liquid triglycerides, polyethyleneglycols, and paraffin hydrocarbons.

Topical dosage forms include, but are not limited to, creams, lotions,ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, andother forms know to a person of ordinary skill in the art. Suitableformulations include, without limitation, solutions, suspensions,emulsions, creams, ointments, powders, liniments, and salves.

Transdermal and mucosal dosage forms can include, but are not limitedto, ophthalmic solutions, patches, sprays, aerosols, creams, lotions,suppositories, ointments, gels, solutions, emulsions, or suspensions.Dosage forms suitable for treating mucosal tissues within the oralcavity can be formulated as mouthwashes, as oral gels, or as buccalpatches.

The disclosed PPAR agonists can be formulated for parenteraladministration, such as, for example, by intraarticular (in the joints),intravenous, intraarterial, intramuscular, intratumoral, intradermal,intraperitoneal, and subcutaneous routes. Examples of parenteral dosageforms include, but are not limited to, solutions ready for injection,dry products ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions. In addition, controlled-release parenteral dosage forms canbe prepared. Suitable materials for such administration include sterilewater; saline solution; glucose solution; aqueous vehicles, such assodium chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose, Sodium Chloride Injection, Lactated Ringer's Injection; ethylalcohol, polyethylene glycol, and propylene glycol; non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate;aqueous and non-aqueous, isotonic sterile injection solutions, which cancontain antioxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.In the practice of this disclosure, compositions can be administered,for example, by intravenous infusion, orally, topically,intraperitoneally, intravesically or intrathecally. In an independentembodiment, parenteral administration, oral administration, and/orintravenous administration are the methods of administration. Theformulations of compounds can be presented in unit-dose or multi-dosesealed containers, such as ampules and vials.

The pharmaceutical preparation can be in unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The combined administrations contemplate co-administration, usingseparate formulations or a single pharmaceutical formulation, andconsecutive administration in either order, wherein, in someembodiments, there is a time period while both (or all) active agentssimultaneously exert their biological activities.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g. the subject, the disease, the disease state involved,the particular treatment, and whether the treatment is prophylactic).Treatment can involve daily or multi-daily or less than daily (such asweekly or monthly etc.) doses over a period of a few days to months, oreven years. For example, a therapeutically effective amount of one ormore compounds disclosed herein can be administered in a single dose,twice daily, weekly, or in several doses, for example daily such as two,three or four times daily, or during a course of treatment. Thedisclosed PPAR agonists may be administered substantially continuouslytoo, such as by using a transdermal delivery system. In a particularnon-limiting example, treatment involves once daily dose or twice dailydose. However, a person of ordinary skill in the art would immediatelyrecognize appropriate and/or equivalent doses looking at dosages ofapproved compositions for treating a PPARδ related disease using thedisclosed PPAR agonists for guidance.

The pharmaceutical compositions that include one or more compoundsdisclosed herein can be formulated in unit dosage form, suitable forindividual administration of precise dosages. In one non-limitingexample, a unit dosage contains from about 1 mg to about 50 g of one ormore compounds disclosed herein, such as about 10 mg to about 10 g,about 100 mg to about 10 g, about 100 mg to about 7 g, about 200 mg toabout 10 g, or about 200 mg to about 5 g. In other examples, atherapeutically effective amount of one or more compounds disclosedherein is from about 0.01 mg/kg to about 500 mg/kg, for example, about0.5 mg/kg to about 500 mg/kg, about 1 mg/kg to about 100 mg/kg, or about1 mg/kg to about 50 mg/kg. In other examples, a therapeuticallyeffective amount of one or more compounds disclosed herein is from about1 mg/kg to about 20 mg/kg, such as about 2 mg/kg to about 5 mg/kg. Insome embodiments, about 3 mg/kg or 10 mg/kg can be used.

V. Methods

Provided herein are methods of activating PPARδ. Such methods caninclude contacting a PPARδ protein with an effective amount of acompound or composition provided herein, thereby activating PPARδ. Insome embodiments, the contacting is performed in vitro. In otherembodiments, the contacting is performed within a subject, such as ahuman or other mammalian subject (such as a veterinary subject, forexample a cat, dog, mouse, or rat), for example by administering a PPARagonist disclosed herein to the subject. In some embodiments, thecompound or composition is administered ton a healthy subject. In someembodiments, the subject is a sedentary or immobilized subject. In otherembodiments, the subject is an exercising subject, such as one whoexercises for at least 20 minutes, at least 30 minutes, at least 45minutes, or at least 60 minutes, at least 2, at least 3, or at least 4days per week. In some embodiments, a healthy subject is also anexercising subject.

In some examples, contacting a PPARδ protein in vitro or in vivo with aneffective amount of one or more compounds or compositions providedherein, increases PPARδ activity by at least 10%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 100%, at least 200%, at least300%, at least 400%, or even at least 500%, for example as compared toan amount of PPARδ activity in the absence of the compound/composition.Methods of measuring PPARδ activity are known, and specific examples areprovided herein (e.g., measuring expression of PPARδ at the protein ornucleic acid level, measuring Beta oxidation levels, creatine kinaselevels, pentose phosphate shunt in liver, blood glucose levels andmethods provided in Wang et al., PLos Biol. 2(10):e294, 2004 and Lee etal., PNAS 103:3444-9, 2006).

In some embodiments, the subject recovers from acute injury followingadministration of the PPAR agonist.

In some embodiments, activating PPARδ within the subject byadministration of a PPAR agonist disclosed herein (or compositioncontaining the PPAR agonist) increases or maintains muscle mass ormuscle tone (such as a skeletal or cardiac muscle) in the subject (suchas in a healthy subject or a sedentary subject). For example, activatingPPARδ within the subject can increase muscle mass, muscle tone, or both,in the subject. In some examples, administering an effective amount ofone or more PPAR agonist compounds or compositions provided hereinincreases muscle mass, muscle tone, or both, by at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, at least 80%, at least 90%, at least 95%, at least 100%, at least200%, at least 300%, at least 400%, or even at least 500%, for exampleas compared to an amount of PPARδ activity in the absence of thecompound/composition. Methods of measuring muscle mass and muscle toneare known, and specific examples are provided herein (e.g., see methodsprovided in WO 2009/086526).

In other embodiments, activating PPARδ within the subject (such as ahealthy subject or a sedentary subject) maintains muscle mass, muscletone, or both, in the subject. In some examples, administering aneffective amount of one or more PPAR agonist compounds or compositionsprovided herein maintains muscle mass, muscle tone, or both, such thatthe amount of muscle mass, muscle tone or both, does not change by morethan 1%, for example no more than 2%, no more than 3%, no more than 4%,no more than 5%, no more than 6%, no more than 7%, no more than 8%, nomore than 9%, no more than 10%, or no more than 15%, for example ascompared to an amount of muscle mass, muscle tone, or both in theabsence of the compound/composition. Methods of measuring muscle massand muscle tone are known, and specific examples are provided herein(e.g., see methods provided in WO 2009/086526).

Thus, the disclosed PPAR agonists and compositions containing such canbe used to increase or maintain muscle mass or muscle tone (or both) ina subject. For example, the disclosed PPAR agonists and compositionscontaining such can be used to increase or maintain muscle mass ormuscle tone (or both) in a subject following an injury, following aperiod of immobilization (for example confinement to a bed orwheelchair) or immobilization of a body part (for example immobilizationof an appendage or joint due to a broken bone, joint replacement, tendontear, surgery, and the like), which events can result in a loss ofmuscle mass and/or muscle tone. The method includes administering to thesubject a therapeutically effective amount of one or more compoundsprovided herein. In some embodiments, the subject is a sedentary orimmobilized subject. In other embodiments, the subject is an exercisingsubject.

Methods of treating or preventing a PPARδ-related disease or conditionin a subject in need thereof are provided. The methods can includeadministering to the subject a therapeutically effective amount of oneor more compounds or compositions provided herein. In some embodiments,the PPARδ-related disease is a vascular disease (such as acardiovascular disease or any disease that would benefit from increasingvascularization in tissues exhibiting impaired or inadequate bloodflow). In other embodiments, the PPARδ-related disease is a musculardisease, such as a muscular dystrophy. Examples of muscular dystrophyinclude but are not limited to Duchenne muscular dystrophy, Beckermuscular dystrophy, limb-girdle muscular dystrophy, congenital musculardystrophy, facioscapulohumeral muscular dystrophy, myotonic musculardystrophy, oculopharyngeal muscular dystrophy, distal musculardystrophy, and Emery-Dreifuss muscular dystrophy. In some embodiments,the PPARδ-related disease or condition is a demyelinating disease, suchas multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacherdisease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy,or Guillian-Barre syndrome.

In some embodiments, the PPARδ-related disease is a metabolic disease.Examples of metabolic diseases include but are not limited to obesity,hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia,hypercholesterolemia, dyslipidemia, Syndrome X, and Type II diabetesmellitus.

Other PPARδ-related diseases that can be treated or prevented with thedisclosed PPAR agonists (or compositions containing such compound),include but are not limited to one or more of the following diseases:(1) a muscle structure disorder, such as Bethlem myopathy, central coredisease, congenital fiber type disproportion, distal muscular dystrophy(MD), Duchenne & Becker M D, Emery-Dreifuss M D, facioscapulohumeral MD,hyaline body myopathy, limb-girdle MD, a muscle sodium channeldisorders, myotonic chondrodystrophy, myotonic dystrophy, myotubularmyopathy, nemaline body disease, oculopharyngeal MD, and stress urinaryincontinence; (2) a neuronal activation disorder, such as amyotrophiclateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome,Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nervelesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnarnerve palsy, toxic myoneural disorder, (3) a muscle fatigue disordersuch as chronic fatigue syndrome, diabetes (type I or II), glycogenstorage disease, fibromyalgia, Friedreich's ataxia, intermittentclaudication, lipid storage myopathy, MELAS, mucopolysaccharidosis,Pompe disease, thyrotoxic myopathy, (4) a muscle mass disorder such as,cachexia, cartilage degeneration, cerebral palsy, compartment syndrome,critical illness myopathy, inclusion body myositis, muscular atrophy(disuse), sarcopenia, steroid myopathy, and systemic lupuserythematosus, (5) a mitochondrial disease such as, Alpers's Disease,CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome(KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrialmyopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes,MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenicmuscle weakness, ataxia, and retinitis pigmentosa, and Pearson Syndrome,(6) a beta oxidation disease such as, systemic carnitine transporter,carnitine palmitoyltransferase (CPT) II deficiency, very long-chainacyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzymedeficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,short-chain acyl-CoA dehydrogenase (SCAD) deficiency,riboflavin-responsive disorders of β-oxidation (RR-MADD), (7) ametabolic disease such as, hyperlipidemia, dyslipidemia,hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia,LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDLhyperproteinemia, dyslipoproteinemia, apolipoprotein A-Ihypoproteinemia, atherosclerosis, disease of arterial sclerosis, diseaseof cardiovascular systems, cerebrovascular disease, peripheralcirculatory disease, metabolic syndrome, syndrome X, obesity, diabetes(type I or II), hyperglycemia, insulin resistance, impaired glucosetolerance, hyperinsulinism, diabetic complication, cardiacinsufficiency, cardiac infarction, cardiomyopathy, hypertension,non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis(NASH), thrombus, Alzheimer disease, neurodegenerative disease,demyelinating disease, multiple sclerosis, adrenal leukodystrophy,dermatitis, psoriasis, acne, skin aging, trichosis, inflammation,arthritis, asthma, hypersensitive intestine syndrome, ulcerativecolitis, Crohn's disease, and pancreatitis, (8) a cancer such as, cancerof the colon, large intestine, skin, breast, prostate, ovary, or lung;(9) a vascular disease such as peripheral vascular insufficiency,peripheral vascular disease, intermittent claudication, peripheralvascular disease (PVD), peripheral artery disease (PAD), peripheralartery occlusive disease (PAOD), and peripheral obliterativearteriopathy; (10) an ocular vascular disease such as, age-relatedmacular degeneration (AMD), stargardt disease, hypertensive retinopathy,diabetic retinopathy, retinopathy, macular degeneration, retinalhaemorrhage, or glaucoma; or (11) a muscular eye disease such as,strabismus (crossed eye/wandering eye/walleye ophthalmoparesis),progressive external ophthalmoplegia, esotropia, exotropia, a disorderof refraction and accommodation, hypermetropia, myopia, astigmatism,anisometropia, presbyopia, a disorders of accommodation, or internalophthalmoplegia. Thus, in some examples, the subject treated has or isat risk for developing one or more of these diseases.

VI. Working Examples

Skeletal muscle relies on the resident progenitor cells, the satellitecells, for postnatal growth and regeneration. Therefore, maintaining anadequate number and proper function of satellite cells is critical formuscle to appropriately response to damage. While endurance exercisepromotes adaptive responses in the muscle, including an increase in thesatellite cell number, it is not known whether transcriptionallydirected “endurance exercise training” has similar effects. Here it isshown that mice harboring constitutively active PPARδ in skeletal muscledisplayed an accelerated regenerative process in muscle after an acuteinjury. Gene expression analyses showed earlier resolution of theinflammatory response and induction of myogenic markers, indicating thatPPARδ activation induces a temporal shift in the regenerative process.Notably, a significant increase in the number of satellite cells wasfound in mice with constitutively active PPARδ expressed in skeletalmuscle, consistent with the observed increase in proliferating cellnumber after the injury. PPARδ activation induced the expression ofFGF1, which is known to be involved in muscle development andregeneration. In particular, PPARδ up-regulates FGF1a isoform, which maybe responsible for supporting cell proliferation and reestablishment ofvasculature to augment the regenerative process. Furthermore, therestoration of fiber integrity was improved in wild-type mice afteracute treatment with the PPARδ synthetic ligand, GW501516. Collectively,these findings allude to the therapeutic potential of PPARδ, toaccelerate the recovery from acute muscle injury. GW501516 is4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid (also known as “GW501516,” “GW-501,516,” “GW1516,” “GW” orGSK-516), and has a structure:

Activation of peroxisome proliferator activated receptor 8 (PPARδ)induces a fiber type switch toward a more oxidative phenotype, alteringboth metabolic and functional output of the muscle (Wang et al., PLoSBiol 2(10):e294. Erratum in: PLoS Biol. 2005 January; 3(1):e61 (2004);Luquet et al., FASEB J 17(15):2299-2301 (2003)). Specifically,PPARδ-mediated muscle remodeling translates into supernatural physicalendurance, and protection against diet-induced obesity and symptoms ofmetabolic disorders that ensue (Wang et al., PLoS Biol 2(10):e294.Erratum in: PLoS Biol. 2005 January; 3(1):e61 (2004); Wang et al., Cell113:159-170 (2003)). Furthermore, pharmacological activation of PPARδand exercise training synergistically enhance oxidative fibers andrunning endurance (Narkar V A et al., Cell 134(3):405-415 (2008)).Exercise confers a myriad of healthful benefits to the body, includingimprovement of atrophic and disease conditions (Nicastro et al., Braz JMed Biol Res 44(11):1070-9 (2011); Markert et al., Muscle Nerve43(4):464-78 (2011)). Recently, endurance exercise alone has been shownto improve ageing induced decrease in satellite cell number and theirmyogenic capacity (Shefer et al., PLoS One 5(10):e13307 (2010)).

It is demonstrated herein that both genetic and pharmacologicalactivation of PPARδ promote muscle regeneration in an acute thermalinjury mouse model. PPARδ activation during regeneration expeditesresolution of inflammatory response and restoration of contractileproteins. Interestingly, acute pharmacological activation of PPARδ byoral administration of a synthetic ligand, GW501516, is sufficient toconfer similar benefits during muscle regeneration after an acuteinjury. Based on these observations, a novel role of PPARδ during adultmuscle regeneration and its use as a therapeutic target to enhanceregenerative efficiency of skeletal muscle is provided.

Example 1 Experimental Procedures

A. Animals

VP16-PPARδ mice (Wang et al., Cell 113:159-170 (2003)) were bred toCB6F1 strain (Jackson Laboratories) and used as heterozygotes inexperiments. The non-transgenic littermates served as controls. Allexperiments were performed when animals were 8 weeks of age. Nestin-GFPmice (Mignone et al., J Comp Neurol 469(3):311-324 (2004)) were kindlyprovided by Dr. Fred Gage at the Salk Institute for

Biological Studies.

B. Freeze burn injury Tibialis anterior (TA) muscles were injuredaccording to previously published methods with a few modifications(Brack et al., Science 317(5839):807-810 (2007)). A stainless steel 1 gweight (Mettler-Toledo) equilibrated to the temperature of dry ice wasplaced directly on the exposed TA for 10 seconds. Following the thermalinjury, incision was closed using VetBond (3M). All injury procedureswere performed on the left leg, and the right leg was used as control.

C. Histology

Animals were perfused with 15 mL of ice-cold PBS followed immediately by20 mL of 10% saline buffered formalin. TA muscles were excised andimmersed in 4% paraformaldehyde for at least 48 hours at 4° C. Tissueswere dehydrated by exposure to a series of solutions with increasingpercentage of ethanol. Dehydrated tissues were cleared in xylene andallowed for paraffin to permeate over night at 60° C. Tissues were thenembedded in plastic molds.

Paraffin embedded tissue blocks were sectioned at 7 μm thick on LeicaJung 2500 Microtome. Sections were stained with hematoxylin and counterstained with 1% eosin. Slides were dried and mounted with Entellanmounting media (EMS). Three random non-overlapping fields werephotographed for analysis. Regenerating fiber number was measured bycounting the number of discernible muscle fibers with centralizedmyonuclei (Ge et al., Am J Physiol Cell Physiol 297(6):C1434-1444(2009)). Regenerating fiber cross sectional area (CSA) was measuredusing Image J software.

D. Evans Blue dye staining

Injured animals were injected with Evans Blue dye according publishedprotocol (Hamer et al., J Anat 200(Pt 1):69-79 (2002)). Sterile 1% w/vEvans Blue dye in PBS was intraperitoneally injected at 1% volumerelative to the body mass of an animal. 7 hours after the injection,injured TA muscles were harvested and snap-frozen by isopentanequenching in liquid nitrogen. Frozen sections were cut in 10 μmthickness, fixed in ice-cold acetone, dipped in xylene and mounted withDPX. Proportion of the stained area over the total area was measuredusing ImageJ software.

E. BrdU Labeling

50 mg/kg body weight of BrdU (Sigma) was injected intraperitoneally assolution of 10 mg/mL BrdU in saline. TA muscles were harvested at 7 daysafter injury and processed for paraffin sections as described above.BrdU incorporation was visualized using the BrdU Labeling and DetectionKit I (Roche) and BrdU+ nuclei were counted and represented as aproportion of total nuclei in a field.

F. RT-QPCR

Whole or partial tissues were homogenized by Polytron probe homogenizerin Trizol reagent (Invitrogen). Total RNA was extracted from thehomogenates according to the manufacturer's protocol. 1 μg ofDNase-treated total RNA was reverse transcribed using Superscript IIReverse Transcriptase (Invitrogen) according to the manufacturer'sinstructions. cDNAs were diluted 1/40 with ddH₂O and used as templatesin RT-QPCR reactions with SYBRGreenER qPCR SuperMix detection system(Invitrogen). Samples were prepared in technical triplicates andrelative mRNA levels were calculated by using the standard curvemethodology and normalized against GAPDH mRNA levels in the samesamples.

G. Myofiber Isolation

Either whole or partial gastrocnemius muscle was digested in 2%collagenase I (Sigma) in DMEM with 10% FBS for 60 minutes at 37° C.Muscle tissue was further mechanically dispersed by triturating in afire polished wide bore Pasteur pipet. Liberated fibers were washed intwo changes of PBS with 10% FBS and finally mounted on glass slides withVectashield mounting media (Vector Labs).

H. Isolation of satellite cells

Satellite cells were harvested from TA of 8 weeks old animals accordingto published protocols with some modifications (Day et al. (2007)Nestin-GFP reporter expression defines the quiescent state of skeletalmuscle satellite cells. Dev Biol 304(1):246-259). Muscles were removedand washed briefly in DMEM on ice. They were then minced into a fineslurry with a razor blade on a 60 mm culture dish over ice. Mincedmuscles were transferred to one well of a 6-well plate containing 5 mlof 450KPU/ml pronase in DMEM. The tissues were digested at 37° C./5% CO₂for 60 minutes. After digestion, tissues were vigorously triturated 20times through 10 ml serological pipet. Digested tissues were filteredthrough a 40 micron cell strainer and washed with an equal volume ofDMEM with 20% horse serum. Cells were spun down at 1000 g for 10 minutesand resuspended in sorting buffer (DMEM with 10% FBS). Cells wereseparated from larger debris using a 20%/60% Percoll gradient(Yablonka-Reuveni Z et al. (1987) Isolation and clonal analysis ofsatellite cells from chicken pectoralis muscle. Dev Bio 119: 252-259).GFP positive cells were sorted on BD FACSAria II sorter.

Example 2 Muscle Specific Activation of PPARδ Confers RegenerativeAdvantage

While it has been shown that the majority of the metabolic genes aredown regulated in injury, PPARδ expression was induced over 2 fold at 2days after the injury (Warren et al. (2007) Mechanisms of skeletalmuscle injury and repair revealed by gene expression studies in mousemodels. J Physiol. 582.2: 825-841, FIG. 1A). This injury dependentup-regulation of PPARδ strongly suggested a possible role for PPARδduring the early part of the regenerative process.

Freeze burn injury was used to elicit the regenerative program, whichhas been shown to model the standard course of the regenerativeresponse, including satellite cell activation (Karpati and Molnar.“Muscle fibre regeneration in human skeletal muscle diseases.” In:Schiaffino S, Partridge T (eds). Skeletal muscle repair andregeneration. Springer, Dordrecht, 2008). Additionally, since the injuryis directly applied to the surface of the muscle, it is highly localizedand reproducible.

Using Evans Blue dye uptake as a marker of myofiber damage, fiberintegrity was histologically assessed. The freeze burn injury does notincapacitate the animals and the damaged fibers restore original crosssectional area by 21 days after the injury (FIG. 1J).

By comparing the proportion of stained fibers within the cross sectionalarea (CSA) of the injured muscle 5 days after the injury, the degree ofdamage was quantified. At 5 days after the injury, VP16-PPARδ (TG)animals show significantly less dye uptake, indicative of enhanced fiberregeneration, over the wildtype (WT) animals (FIGS. 1C and D). While 14%of the total CSA shows dye uptake in WT muscle, only 5% of the total CSAof TG muscle show dye uptake (n=8 WT; n=5 TG; p=0.001) (FIG. 1D). At 12and 36 hours after the injury, however, both WT and TG animals showedsimilar proportions of stained area (50.6% and 47.4% (p=0.67), and 38.5%and 43.3% (p=0.23), respectively) (FIGS. 1E and 1F). Similar level ofdye uptake shortly after the injury shows that both WT and TG animalsinitially sustain similar degree of damage from the injury and suggeststhat PPARδ activation does not confer protection from damage. Instead,the reduction in Evans Blue dye uptake observed 5 days after the injurysuggests that the muscle specific PPARδ activation promotes restorationof fiber integrity after the injury.

The morphological hallmarks of regenerating fibers were determined for adetailed analysis of the process. H&E stained transverse sectionsthrough the injured area were examined at 3, 5 and 7 days post injury.At 3 days after the injury, both WT and TG animals showed similardegrees of degeneration defined as necrosing fibers surrounded byinfiltrating monocytes (FIG. 1G). No regenerating fibers, characterizedby a small round shape and centralized nuclei, were discernible at 3days in WT animals, but a notable few were seen in TG animals (arrows,FIG. 1G). By day 5 after the injury, obvious differences are seen. In WTanimals, small regenerating fibers were visible but necrosing fibers andmonocytes were still prevalent at the site of the injury (arrowheads,FIG. 1G). While in the TG animals, the injury site shows an orderlyarrangement of small regenerating fibers. Quantification of regeneratingfiber number and CSA reveals that by 5 days post injury, TG animals showsignificant regenerative advantage over their WT counterparts. Both CSAof the regenerating fibers and the number of regenerating fibers weresignificantly greater for TG animals at 43.5% (n=5 or 6; p<0.03) and33.0% (n=11 or 12; p<0.001), respectively (FIGS. 1H and 1I). By day 7post injury, the damage site appears architecturally similar between WTand TG animals, where both show a field of immature regenerating fiberswithout the infiltrating immune cells. However, quantification of theregenerating fibers revealed a regenerative advantage of the TG animalsin the number of nascent regenerating fibers (FIG. 1H). At 21 days afterthe injury, both WT and TG animals have restored their fiber size andnumber to that of the uninjured level (FIG. 1J). These data demonstratethat the muscle specific activation of PPARδ bestows significantregenerative advantage, most prominently observed in the early stages ofthe regenerative process.

Example 3 PPARδ Activation Leads to Temporal Shift, Thus IncreasedEfficiency, of the Muscle Regenerative Process

Skeletal muscle regeneration is an intricately orchestrated processinvolving a variety of cell types. For example, immune cells, bothneutrophils and macrophages, are necessary for the proper progression ofregenerative process (Zacks et al., Muscle Nerve 5:152-161 (1982);Grounds et al., Cell Tissue Res 250:563-569 (1987); Teixeira et al.,Muscle Nerve 28(4):449-459 (2003); Summan et al., Am J Physiol RegulIntegr Comp Physiol 290:R1488-R1495 (2006); Contreras-Shannon et al., AmJ Physiol Cell Physiol 292:C₉₅₃-967 (2007); Segawa et al., Exp Cell Res314(17):3232-3244 (2008)). Additionally, various cytokines are necessaryto promote chemotaxis of monocytes and also to directly regulate theactivities of myogenic cells (Warren et al., Am J Physiol Cell Physiol286(5):C1031-1036 (2004); Yahiaoui et al., J Physiol 586:3991-4004(2008); Chazaud et al., JCB 163(5):1133-1143 (2003)). Therefore, thetemporal expression profiles of genes associated with various aspects ofthe regenerative process were determined.

Global, injury-specific gene expression changes were identified in TAmuscles by microarray. Comparing the gene expression profiles of injuredTG and WT muscle 3 days post-injury, 3257 genes with altered expressionwere identified, of which 1375 were down regulated and 1882 were upregulated. Notably, genes involved in myogenesis and remodeling wererobustly up-regulated by PPARδ activation while those involved ininflammatory response were down regulated in injured TG muscles (FIGS.2A and B). Additionally, genes involved in developmental processes,angiogenesis and anti-apoptotic processes emerged from the analysis(FIG. 2A). Relative expressions of regeneration markers revealdown-regulation of early makers (inflammatory genes) and up-regulationof regenerative/remodeling genes (myogenic, vascularization, ECM genes)in TG animals 3 days post injury (FIG. 2B). Collectively, PPARδactivation appears to control a network of genes directly involved inmyogenesis, as well as genes involved in remodeling and the repairprocesses after an injury.

Underlying the phasic progression of the regenerative program is atemporally coordinated program of gene expression changes that affect avariety of contributing processes. In order to validate andtemporally-expand the microarray data, expression of CD68 (aninflammation marker) and MyoD (a marker of myogenesis) were measured byQ-PCR at several time points over the 7 day period post injury (FIGS. 2Cand 2D). A temporal shift in the expression patterns of regenerativemarkers for TG animals compared to their WT littermates was observed. TGanimals showed a rapid, most robust induction of CD68, that wassubsequently down regulated earlier than in the WT animals.Interestingly, inflammatory markers studied here peaked at similarlevels between the two genotypes, which indicates that TG animals do notcompletely suppress their inflammatory responses. Instead, it appearsthat the TG animals resolve the inflammatory responses more efficiently,which is consistent with the accelerated restoration of musclemorphology observed. TG animals also show higher expression of perinatalmyosin heavy chain gene, Myh8, at 7 days post injury, indicating moreefficient reassembly of the contractile properties (FIG. 2E). PPARδactivation leads to a temporal shift in the expression patterns ofregenerative markers, which together with the histology data, shows arole of PPARδ in increasing regenerative efficiency.

Example 4 PPARδ Directs Neo-Vascularization Via Regulation of FGF1

This example describes adaptive responses bestowed by PPARδ activationin the muscle which may contribute to the observed beneficial effects onregeneration.

Increased vasculature is one of the hallmarks of oxidative myofibers,which facilitates introduction of immune cells and also supportsincreased number of satellite cells. TG animals show increasedexpression of FGF1 in TA muscle (FIG. 3D). Immunostaining transversesections of uninjured TA from WT and TG animals revealed a 36% increasein the number of CD₃₁+ capillaries per field upon PPARδ activation(FIGS. 3A-B), as well as a significant increase in the expression ofFGF1a. Furthermore, 5 days after injury, TG animals show increasedexpression of CD₃₁, which is indicative of increased vascularity (FIG.3E-F). Notably, FGF1a is a direct PPARδ target gene, as demonstrated bythe PPARδ response element (PPRE)-dependent activation with the PPARδligand, GW501516, in a luciferase reporter assay (FIG. 3G). FGF1 hasbeen shown to be expressed in regenerating fibers in chronic diseasemodels and has been implicated in myogenesis and regeneration (Oliver,Growth Factors. 1992; 7(2):97-106, 1992; Saito, 2000, Muscle Nerve.23(4):490-7). In addition, FGF1 increasing the microvasculature inadipocytes and PPARδ has been shown to directly regulate the expressionof FGF1a isoform (Jonker et al., Nature. 485(7398):391-4, 2012).Therefore, the increased vascularity induced by PPARδ may contribute tothe accelerated regenerative process observed in VP16-PPARδ animals.

Example 5 PPARδ Activation Positively Regulates Quiescent Satellite CellNumber

One of the first events following the injury is the proliferation ofmuscle resident progenitors, the satellite cells. This example describesresults showing that the regenerative advantage observed in TG animalscould be due to altered satellite cell homeostasis.

Nestin expression was used as a marker of satellite cells, andnestin-GFP;VP16-PPARδ double transgenic animals were used to geneticallylabel quiescent satellite cells (SCs) in vivo (Mignone et al., J CompNeurol 469(3):311-324 (2004); Day et al., Dev Biol 304(1):246-259(2007)). Gastrocnemius muscles were enzymatically digested to liberateindividual fibers, then mounted for quantification (FIG. 4A). Whiledouble transgenic animals averaged 1.01 SCs per mm of fiber length,GFP+animals only had 0.15 SCs per mm, a 6.48 fold higher SC content onVP16-PPARδ muscle fiber (FIG. 4B).

Satellite cell activity was measured as myoblast proliferation elicitedby the freeze burn injury in vivo. After the freeze burn injury, BrdUwas intraperitoneally injected at 12 hrs, 24 hrs and 2 days after theinjury, and the muscles were harvested 7 days after the injury. Theratio of BrdU+ to total nuclei was calculated to determine the number ofproliferating cells. TG animals showed 40-60% increase in the number ofBrdU+proliferating cells at all three injection times (FIG. 4C). Theseresults are consistent with the PPARδ-induced increase in the number ofquiescent satellite cells yielding higher numbers of fusion competentmyoblasts, leading to the enhancement of regenerative capacity of themuscle. Interestingly, neither endogenous PPARδ, or the constitutivelyactivate VP16-PPARδ, are significantly expressed in satellite cells(FIGS. 4D and E), indicating that the increase in satellite cell numberin the TG muscle is an indirect consequence of PPARδ activation inmuscle.

Example 6 Acute Pharmacological Activation of PPARδ Confers aRegenerative Advantage

Pharmacological activation of PPARδ has been shown to induce PPARδtarget genes in fast-twitch hind limb muscles (Narkar et al., Cell134(3):405-415 (2008)). To demonstrate that an acute pharmacologicalactivation of PPARδ can modulate the regenerative process after injury,C₅₇BL6J mice were treated with GW501516 (Sundai Chemicals, China) orallyat 5 mg/kg for 4 days prior to, and 5 days after freeze burn injury tothe TA muscle.

Up-regulation of known PPARδ target genes (PDK4, CPT1b, and catalase) inthe TA muscle was confirmed by QPCR, attesting to the successfuldelivery and activity of the PPARδ ligand in the muscle (FIG. 5A). Whilevehicle treated animals showed Evans Blue dye uptake in 7.6% of thecross sectional area (CSA), only 4.9% of the muscle CSA was stained inthe ligand treated animals (FIGS. 5B and 5C). Thus, PPARδ ligand-treatedanimals showed a 34.7% reduction in damaged muscle fibers 5 days afterthe injury, demonstrating that pharmacological activation of PPARδenables accelerated restoration of myofiber integrity after injury.

Consistent with the PPARδ ligand conveying a regenerative advantage,BrdU injection at 48 hours after the injury showed a marked increase inproliferative cell number in the ligand treated muscle, supporting thenotion that PPARδ activation promotes myoblast proliferation afterinjury (FIG. 5D). While the number of quiescent satellite cells was notsignificantly affected by either 9 days or 4 weeks of ligand treatment,satellite cells do not undergo rapid turnover. Thus, the duration ofligand treatment may have been insufficient to affect the numbers ofthese long-lived progenitor cells. Nonetheless, GW501516 treatmentpromoted myoblast proliferation in vivo after the injury, which maycontribute to the accelerated regeneration after the injury.

The expression of inflammatory marker genes was measured after injury byQPCR. While the initial inflammatory responses at 12 hours after injuryare similar with and without PPARδ ligand treatment, a significantreduction in both TNFα and the macrophage marker F4/80 expression wasseen at 3 days post injury in PPARδ ligand treated muscle (FIG. 5E).These results are consistent with the known role of PPARδ as ananti-inflammatory regulator, and corroborate the beneficial findingsobserved in the VP16-PPARδ genetic model.

Example 7 Muscle Specific Activation of PPARδ is Protective AgainstExercise-Induced Injury

WT and TG mice were acclimated to moderate treadmill running (10 m/minfor 15 min) every other day for 1 week. After acclimation, the speed wasgradually increased to 15 m/min and then maintained constant untilexhaustion (week 0). Subsequently, mice were subjected to 4 weeks (5days/week) of exercise training on a treadmill inclined at 5 degreeincline, with progressively increasing intensity and time. At the end ofthe training protocol (week 5), mice were run to exhaustions and serumsamples were taken for the measurement of creatine kinase levels.

WT and VP16-PPARδ (TG) mice were run to exhaustion, and their serumcreatine kinase (CK) levels we measured by ELISA. The levels of CK inthe TG mice were significantly lower than those in WT mice, indicativeof reduced exercise-induced muscle damage (FIG. 6).

Example 8 Muscle Specific Activation of PPARδ Enhances Recovery afterInjury

This example describes adaptive responses bestowed by PPARδ activationin the muscle which may contribute to the observed beneficial effects onregeneration.

Evans Blue staining of transverse sections of injured TA from WT and TGanimals revealed decreased staining in TG muscle at 3 days post injury,consistent with PPARδ activation being beneficial for muscle repair(FIG. 7A). Supporting this notion, endogenous PPARδ is transientlyincreased in the TA muscle after freeze burn injury (FIG. 7B).Furthermore, the temporal expression profile of the inflammatory markerTNFα in wildtype (WT, solid line) and VP16-PPARδ (TG, dashed line) afterinjury was altered, suggesting a more rapid resolution of theinflammatory response in TG muscle (FIG. 7C). Increased vasculature isone of the hallmarks of oxidative myofibers, which facilitatesintroduction of immune cells and also supports increased number ofsatellite cells. TG animals show increased expression of VEGFα at boththe mRNA and protein levels in TA muscle (FIG. 7D-E).

Example 9 Enhanced Notch Signaling in VP16-PPARδ Muscle

Notch signaling is critical for skeletal muscle myogenesis and hasimportant roles in maintaining the muscle stem cell pool and preventingpremature muscle differentiation. To investigate whether constitutivePPARδ activation affects the Notch signaling pathway, we compared theexpression of selected genes in the pathway in TA muscle from WT andVP16-PPARδ transgenic (TG) mice. Microarray analyses identified theupregulation of multiple genes in the Notch pathway in TG muscle (FIG.8A). The PPARδ-induced increase in expression of Jag1, Jag2, Notch3 andNotch4 were confirmed in TA muscle from 2 month old mice by QPCR (FIG.8B). Consistent with the notion that PPARδ activates the Notch pathway,increases in Notch1 and Hes1 expression were seen in mice afterpharmacological activation via a 9 day treatment with the PPARδ ligand,GW501516 (FIG. 8C). Furthermore, examination of 12 month old TG micerevealed increased expression of Jag 1, Hey1, and Notch3, consistentwith the sustained activation of the Notch pathway in VP16-PPARδ mice(FIG. 8D).

Example 10 Pharmacokinetics of PPARδ Ligands

The oral bioavailability and serum half lives of PPARδ ligands werecompared in mice. The pharmacokinetics of PPARδ ligands delivered orally(10 mg/kg p.o.) and intravenously (3 mg·kg i.v.) were determined by massspectrometry. The circulating serum levels of novel PPARδ ligands (FIGS.9A, B, C, E) at indicated times after drug delivery, as compared withGW501516 (FIG. 9D).

In summary, PPARδ activation expedites skeletal muscle regenerationfollowing an acute thermal injury. VP16-PPARδ transgenic animals showedincreased satellite cell proliferation at the early phase of theregenerative process, which subsequently translated into increased CSAand number of nascent regenerating fibers. Most interestingly, musclespecific over expression of PPARδ seems to increase the residentsatellite cell pool. Increased satellite cell population on a musclefiber seems to contribute to the accelerated resolution of the injury.These findings unveil a novel role for PPARδ in the maintenance ofskeletal muscle; as a potential therapeutic target for acceleratedrestoration of muscle mass after an acute injury and other atrophicconditions.

Notably, PPARδ activation seems to promote rapid emergence of nascentfibers after the injury. There being no evidence of hyperplasia at 21days after the injury when the regenerative process is essentiallycomplete, it is concluded that the additional nascent fibers efficientlyfuse with each other to restore mature fibers (Karpati G, Molnar M J inSkeletal muscle repair and regeneration, eds Schiaffino S, Partridge T(Springer, Dordrecht), (2008)). While IGF-1 and myostatin seem to relyon fiber hypertrophy to augment regenerative progress, PPARδ seems toemploy a unique way to promote regeneration (Menetrey et al., J BoneJoiny Surg Br 82(1):131-7 (2000); Wagner et al., Ann Neurol 52(6): 832-6(2002); Bogdanovich et al., Nature 420(6914):418-21 (2002)). Underlyingthis difference may be the increased number of quiescent satellitecells. Higher number of progenitor cells leads to the increase in postinjury proliferating cells and consequent increase in the number ofnascent fibers. While various growth factors and chemokines, includingIGF-1 and myostatin, have been shown to enhance proliferation ofsatellite cells and promote regeneration, it is unclear whether any ofthem positively regulate the number of quiescent satellite cells(Husmann I et al., Cytokine Growth Factor Rev 7(3):249-258 (1996);McCroskery et al., J Cell Biol 162(6):1135-1147 (2003); Musaro et al.,Nat Genet 27:195-200 (2001); Amthor et al., PNAS 106(18):7479-84(2009)). The findings shown herein indicate a novel role of PPARδ as apositive regulator of satellite cell pool. Interestingly, since rapidcell proliferation was not observed under normal conditions, PPARδmediated satellite cell expansion is transient and tightly regulated,most likely elicited by external stimuli, such as signals for postnatalgrowth and injury. In an adult muscle, satellite cell number is finite,diminishing detrimentally in disease state and aging. It is of greattherapeutic benefit if PPARδ activation can bestow infinite abundance ofsatellite cell population throughout the life of an organism.

While enhancement in regenerative capacity was observed in both geneticand pharmacological models, the inherent differences in the experimentalparameters is acknowledged. Orally administered GW501516 was deliveredsystemically, presumably activating PPARδ in a variety of organs andcell types in the animal. However, in VP16-PPARδ animals, activation ofthe PPARδ receptors is limited to the mature muscle fibers.Additionally, genetic background of the animals may affect theefficiency of regeneration after an injury (Grounds and McGeachie, CellTissue Res 255(2):385-391 (1989); Roberts et al., J Anat 191:585-594(1997)). Extramuscular effects of PPARδ agonist administration mayrequire further investigation when considering clinical use of GW501516to augment muscle injury treatment. Recently, pharmacological activationof PPARδ has been shown to improve sarcolemmal integrity in mdx mice(Miura et al., Hum Mol Genet 18(23):4640-4649 (2009)).

The results herein expand previous understandings of the role of PPARδin muscle physiology. It is shown herein that PPARδ not only controlsrunning endurance and metabolic parameters in the muscle, but also itsregenerative program. PPARδ activation affects multiple facets of theregenerative program, exerting comprehensive but transient effects toexpedite the progress. In view of these findings, PPARδ may bepharmacologically targeted to enhance the regenerative capacity of themuscle after injury and possibly other degenerative conditions wheresatellite cell function is compromised. For example, PPARδ activationcan be used to treat other degenerative conditions such as aging inducedsatellite cell dysfunction and ensuing sarcopenia.

Example 11 PPARδ Activity Screen

Cell Culture and Transfection: CV-1 cells were grown in DMEM+10%charcoal stripped FCS. Cells were seeded into 384-well plates the daybefore transfection to give a confluency of 50-80% at transfection. Atotal of 0.8 g DNA containing 0.64 micrograms pCMX-PPARDelta LBD, 0.1micrograms pCMX.beta.Gal, 0.08 micrograms pGLMH2004 reporter and 0.02micrograms pCMX empty vector was transfected per well using FuGenetransfection reagent according to the manufacturer's instructions(Roche). Cells were allowed to express protein for 48 h followed byaddition of compound.

Plasmids: Human PPARδ was used to PCR amplify the PPARδ LBD. Theamplified cDNA ligand binding domain (LBD) of PPARδ isoform was (PPARδamino acid 128 to C-terminus) and fused to the DNA binding domain (DBD)of the yeast transcription factor GAL4 by subcloning fragments in frameinto the vector pCMX GAL (Sadowski et al. (1992), Gene 118, 137)generating the plasmids pCMX-PPARDelta LBD. Ensuing fusions wereverified by sequencing. The pCMXMH2004 luciferase reporter containsmultiple copies of the GAL4 DNA response element under a minimaleukaryotic promoter (Hollenberg and Evans, (1988) Multiple andcooperative trans-activation domains of the human glucocorticoidreceptor Cell 55, 899). pCMXβGal was generated.

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple inconcentrations ranging from 0.001 to 100 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin at least two separate experiments.

Luciferase assay: Medium including test compound was aspirated andwashed with PBS. 50 μl PBS including 1 mM Mg++ and Ca++ were then addedto each well. The luciferase assay was performed using the LucLite kitaccording to the manufacturer's instructions (Packard Instruments).Light emission was quantified by counting on a Perkin Elmer Envisionreader. To measure 3-galactosidase activity 25 μl supernatant from eachtransfection lysate was transferred to a new 384 microplate.Beta-galactosidase assays were performed in the microwell plates using akit from Promega and read in a Perkin Elmer Envision reader. Thebeta-galactosidase data were used to normalize (transfection efficiency,cell growth etc.) the luciferase data.

Statistical Methods: The activity of a compound is calculated as foldinduction compared to an untreated sample. For each compound theefficacy (maximal activity) is given as a relative activity compared toGW501516, a PPARδ agonist. The EC₅₀ is the concentration giving 50% ofmaximal observed activity. EC₅₀ values were calculated via non-linearregression using GraphPad PRISM (GraphPad Software, San Diego, Calif.).

Example 12 Synthetic Preparation of Compound Embodiments Abbreviations

rt room temperatureEDCI.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideHBTU O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphateHOBt 1-hydroxybenzotriazole

Reaction Step 1—Aryl Etherification

Material Source Mol. Wt. Density Equiv mmol Amount Ethyl-bromo-hexanoateSigma-Aldrich 223.12 1.258 1.0 10.0 1.77 mL SalicylaldehydeSigma-Aldrich 122.12 1.166 1.0 10.0 1.05 mL Cesium carbonateSigma-Aldrich 325.82 — 1.2 12.0 3.91 g DMA (solvent) Sigma-Aldrich — — —— 17.18 mL Ethyl 6-(2-formyl-phenoxy)hexanoate Product 264.32 — (1.0)(10.0) (2.64 g)

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Thirteen (13) identicalreactions at the 10 mmol scale were setup in parallel and processed inserial, as follows:

All three (3) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) ethyl-bromo-hexanoate (1.77 mL), (2)salicylaldehyde (1.05 mL), (3) cesium carbonate (Cs₂CO₃) (3.91 g) and(4) reaction solvent DMA (17.18 mL). Care was taken to dispense theN-N-dimethylacetamide (DMA) solvent in such a manner so as to wash downthe vial walls of reactant or solid base. To each vial was added amagnetic stir bar and fitted with a crimp seal cap and adapter collar.The reactions were than process in the MW Reactor for 10 minutes (attemperature) at 140° C. with mixing. Following standard ramp up, fixedhold time at temperature and cool down, samples were kept sealed atambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 800 mL was added. To this was added 800 mL of1.0 N NaOH solution, and the two layers were vigorously shaken and mixedand then separated. The NaOH aqueous layer was back-extracted 3×250 mLwith EtOAc, and all the organic layers were combined (about 750 mL) andwashed with 800 mL of 1.0 M citric acid solution. The citric acid layerwas again back extracted with EtOAc (3×250 mL), and the organic layerswere again combined (about 1.5 L) and washed (3×500 mL) with brine(saturated NaCl), dried over sodium sulfate (Na₂SO₄) and concentrated todryness in vacuo. Silica gel TLC (3:1 Hexanes-EtOAc) R_(f)=0.34(product), R_(f)=0.45, 0.25 (trace impurities). Theoreticalyield=13×2.64 g or 34.32 g (130 mmol). Isolation and Observedyield=33.30 g, (33.30 g/34.32 g x 100)=97%. NMR (¹H, ¹³C, COSY) and LCMS(ESI+/−) conform to structure.

Reaction Step 2-Reductive Amination

Material Source Mol. Wt. Density Equiv. mmol Amount Ethyl 6-(2-formyl-Reaction1 Product 264.32 — 1.0 10.0 2.6557 g phenoxy)hexanoateCyclopropylamine Sigma-Aldrich 57.09 0.814 1.1 11.0 769 μL Acetic acid,gl. Sigma-Aldrich 60.04 1.04 6.6 66.0 3.81 mL NaBH(OAc)₃ Sigma-Aldrich211.94 — 2.2 22.0 4.67 g DCE (solvent) Sigma-Aldrich — — — — 10.0 mLEthyl 6-(2-((cyclo- Product 304.42 — (1.0) (10.0) (3.04 g)propylamino)methyl) phenoxy)hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twelve (12) identicalreactions at the 10 mmol scale were setup in parallel and processed inserial, as follows:

All four (4) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) Ethyl 6-(2-formylphenoxy)hexanoate (about2.66 g), (2) cyclopropylamine (769 μL), (3) acetic acid (AcOH) (3.81 mL)and 50% of the reaction solvent 1,2-dichloroethane (DCE), (4) sodiumtriacetoxyborohydride (4.67 g) and (5) the remaining 5 mL portion ofDCE. Care was taken to dispense the DCE solvent in such a manner so asto wash down the vial walls of reactant or solid reducing agent. To eachvial was added a magnetic stir bar and fitted with a crimp seal cap andadapter collar. The reactions were than process in the MW Reactor for 10minutes (at temperature) at 120° C. with mixing. Following standard rampup, fixed hold time at temperature and cool down, samples were keptsealed at ambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 1 L was added. To this was added 800 mL ofsaturated NaHCO₃solution, and the two layers were vigorously shaken andmixed and then separated, this extraction was performed an additional 2times (3×800 mL in total). The organic EtOAc layer was then washed withbrine (1×800 mL). The combined bicarb and brine aqueous layers were thenback-extracted 1×200 mL with EtOAc, and all the organic layers werecombined (about 1.4 L) and dried over sodium sulfate (Na₂SO₄) andconcentrated to dryness in vacuo.

Observed crude yield=36.21 g of crude product. Three (3) spots by silicagel TLC (95:5 DCM-MeOH), R_(f)=0.17 (product), R_(f)=0.22 (tertiaryamine by-product), R_(f)=0.08 (unk). Purified by silica gelchromatography, Biotage SP4, 65i column with samplet cartridge. A totalof 3-columns were run, about 12 g of crude loaded into the samplet inMeOH and dried in vacuo. Elution program was as follows: 1 CV @ 99%DCM-1% MeOH, then 10 CV @ gradient 99→90% DCM and 1→10% MeOH, and 2 CV @90% DCM-10% MeOH. Fractions were combined, concentrated and dried undervacuum. Theoretical yield=12×3.04 g or 36.53 g (120 mmol). Isolation andObserved yield=29.28 g, (29.28 g/36.53 g x 100)=80.2%. NMR ¹³C, COSY)and LCMS (ESI+/−) conform to structure.

Reaction Step 3-Aryl amide formation

Material Source Mol. Wt. Density Equiv. Mmol Amount Ethyl 6-(2-((cyclo-Reaction2 Product 304.42 — 1.0 4.42 1.35 g propylamino)methyl)phenoxy)hexanoate 4-bromo-benzoyl chloride Lancaster 219.47 — 1.1 4.861.067 g DIEA (Hunig's base) Sigma-Aldrich 129.25 0.742 2.2 9.72 933 μLDCE (solvent) Sigma-Aldrich — — — — 15.0 mL Ethyl 6-(2-((4-bromo-N-Product 488.41 — (1.0) (4.42) (2.16 g) cyclopropylbenzamido)methyl)phenoxy) hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twenty (20) identicalreactions at the 4.42 mmol scale were setup in parallel and processed inserial, as follows:

All three (3) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) Ethyl 6-(2-((cyclo-propylamino)methyl)phenoxy)hexanoate (about 1.35 g), (2) 4-bromobenzoyl chloride(4-BrBzCl)(1.067 g), (3) DIEA (933 μL), (3.81 mL) and 50% of thereaction solvent 1,2-dichloroethane (DCE), and (4) the remaining 7.5 mLportion of DCE. Care was taken to dispense the DCE solvent in such amanner so as to wash down the vial walls of solid 4-BrBzCl. To each vialwas added a magnetic stir bar and fitted with a crimp seal cap andadapter collar. The reactions were than process in the MW Reactor for 10minutes (at temperature) at 75° C. with mixing. Following standard rampup, fixed hold time at temperature and cool down, samples were keptsealed at ambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 1 L was added. To this was added 800 mL ofsaturated NaHCO₃ solution, and the two layers were vigorously shaken andmixed and then separated, this extraction was performed one additionaltime (2×800 mL in total). The organic EtOAc layer was then washed withbrine (2×800 mL). The combined bicarb and brine aqueous layers were thenback-extracted 1×200 mL with EtOAc, and all the organic layers werecombined (about 1.4 L) and dried over sodium sulfate (Na₂SO₄) andconcentrated to dryness in vacuo.

Observed crude yield=45.3 g of crude product which was an oilysemi-solid. Three (3) spots by silica gel TLC (2:1 Hexanes-EtOAc),R_(f)=0.42 (product), R_(f)=0.50, 0.17 (by-products). Purified by silicagel chromatography, Biotage SP4, 65i column with samplet cartridge. Atotal of 4-columns were run, about 11 g of crude loaded into the sampletin MeOH and dried in vacuo. Elution program was as follows: 1 CV @ 92%Hex-8% EtOAc, then 10 CV @ gradient 92→34% DCM and 8→66% EtOAc, and 2 CV@ 34% Hex-66% EtOAc. Fractions were combined, concentrated and driedunder vacuum. Theoretical yield=20×2.16 g or 43.2 g (88.4 mmol).Isolation and Observed yield=23.02 g, (23.02 g/43.2 g x 100)=53.3%(yields ranging from 50-80% have been obtained depending on the batch of4-BrBzCl and the degree to which this reaction is carried out underanhydrous conditions). NMR (¹H, ¹³C, COSY) and LCMS (ESI+/−) conform tostructure.

Reaction Step 4—Suzuki coupling

Material Source Mol. Wt. Density Equiv. mmol Amount Ethyl6-(2-((4-bromo-N- Reaction3 Product 488.41 — 1.0 4.09 2.00 gcyclopropylbenzamido) methyl)phenoxy) hexanoate Furan-2-boronic acidAlfa Aesar 111.89 — 1.25 5.11 572 mg Pd(PPh₃)₄ Sigma-Aldrich 1155.58 —0.03 0.123 141.8 mg 2.0M Na₃CO₃ aq. Sigma-Aldrich — — 3.0 12.3 6.135 mLDME (solvent) Sigma-Aldrich — — — — 4.6 mL EtOH, 95% (co-solvent)Sigma-Aldrich — — — — 4.6 mL Ethyl 6-(2-((N- Product 475.61 (1.0) (4.09)(1.95 g) cyclopropyl-4-(furan-2- yl)benzamido) methyl)phenoxy) hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Eleven (11) identicalreactions at the 4.09 mmol scale were setup in parallel and processed inserial, as follows:

All four (4) reagents and reaction co-solvents were added to the MW vialin the following sequence; (1) Ethyl6-(2-((4-bromo-N-cyclopropylbenzamido)methyl)phenoxy) hexanoate (about 2g), (2) Furan-2-boronic acid (572 mg), (3) Pd(PPh₃)₄ (141.8 mg), (4) 2.0M sodium carbonate solution (6.135 mL), followed by the co-solvents 95%EtOH and DME (1,2-dimethoxyethane). Care was taken to dispense the DMEsolvent in such a manner so as to wash down the vial walls of solidcatalyst. To each vial was added a magnetic stir bar and fitted with acrimp seal cap and adapter collar. The reactions were than process inthe MW Reactor for 10 minutes (at temperature) at 140° C. with mixing.Following standard ramp up, fixed hold time at temperature and cooldown, samples were kept sealed at ambient temperature until the entirelot was processed. Note, depending on the age of the tetrakis Pdcatalyst (fresh when red, darkens to brown with age) the microwavereaction temperature may need to be increased and the reaction timelengthened. It has been observed that a trace side product increaseswith reaction temp/time and corresponds to the saponified ester, whichis the next and final synthetic step. This ester hydrolysis should beexpected given the excess base in the presence of water and ethanol asco-solvents. Therefore the ethyl ester is not isolate.

The crude reaction mixtures were individually opens and poured out ontoa 800 mL sintered filtration funnel (medium porosity) fitted with a 2 Lside arm Erlenmeyer flask attached to house vacuum. The funnel wascharged with a 2-3″ bed of flash grade silica gel (Silicycle, 60A, 40-63μm, F60 silica gel). A second layer (about 1-2″) of diatomaceous earthfilter aid (Celite 545) was packed on top of the silica gel, to producea binary dry column vacuum chromatography (DCVC) system. A typical CVwas about 100 mL, and each reaction mixture was eluted with 1CV ofchromatography grade THF. The column was washed with 4CV of THF until noreaction product(s) were visible by TLC. The THF mixture wasconcentrated to produce about 25 g of viscous oil isolated, that wasthen taken directly onto the next step. Theoretical yield=11×1.95 g or21.45 g (45.0 mmol). NMR (¹H, ¹³C, COSY) and LCMS (ESI+/−) conform tostructure.

Reaction Step 5—Saponification

Material Source Mol. Wt. Density Equiv. Mmol Amount Ethyl 6-(2-((N-Reaction4 Product 475.61 — 1.0 2.045 972.4 mg cyclopropyl-4-(furan-2-yl)benzamido) methyl)phenoxy) hexanoate LiOH•H₂O Sigma-Aldrich 41.96 —4.89 10 420 mg THF (solvent) Sigma-Aldrich — — — — 15 mL H₂O(co-solvent) Sigma-Aldrich — — — — 5 mL 6-(2-((N-cyclopropyl-4- Product447.52 — (1.0) (2.045) (915.2 mg) (furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twenty-two (22)identical reactions at the 2.045 mmol scale were setup in parallel andprocessed in serial, as follows:

All two (2) reagents and reaction co-solvents were added to the MW vialin the following sequence; (1) crude ethyl6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido) methyl)phenoxy) hexanoatewas dissolved to a volume of 33 mL, 15 mL per reaction vial, and (2)LiOH (hydrate) as a 2 M solution in water, 5 mL per reaction vial. Toeach vial was added a magnetic stir bar and fitted with a crimp seal capand adapter collar. The reactions were than process in the MW Reactorfor 10 minutes (at temperature) at 150° C. with mixing. Followingstandard ramp up, fixed hold time at temperature and cool down, sampleswere kept sealed at ambient temperature until the entire lot wasprocessed.

The crude reaction mixtures were individually opens and poured out ontoa 800 mL sintered filtration funnel (medium porosity) fitted with a 2 Lside arm Erlenmeyer flask attached to house vacuum. The funnel wascharged with a 2-3″ bed of flash grade silica gel (Silicycle, 60A, 40-63μm, F60 silica gel). A second layer (about 1-2″) of diatomaceous earthfilter aid (Celite 545) was packed on top of the silica gel, to producea binary dry column vacuum chromatography system. The dry column wasacid washed (acidified with either 1M citric acid or 1N HCl) with 2×1Lof acid solution. A typical CV was about 100 mL, and each reactionmixture was eluted with 1 CV of 1:1 DCM-THF. The column was washed with4 CV of 1:1 DCM-THF until no reaction product(s) were visible by TLC.The DCM-THF mixture was concentrated to produce about 21 g of viscousoil. This crude product exhibited impurities with R_(f) values close tothat of the desired material. Flash chromatography used four (4) Biotage65i columns on Biotage SP4, loading about 5 g crude. Theoreticalyield=22×915.2 mg or 20.13 g (45.0 mmol). Isolation and Observedyield=11.54 g, (11.54 g/20.13 g×100)=57.3%. NMR ¹³C, COSY) and LCMS(ESI+/−) conform to structure.

Reaction Step 6—Salt formation

Material Source Mol. Wt. Density Equiv. mmol Amount6-(2-((N-cyclopropyl-4-(furan- Reaction5 Product 447.52 — 1.0 25.7811.54 g 2-yl)benzamido) methyl)phenoxy)hexanoic acid NaOH Sigma-Aldrich40.00 — 1.1 28.36 1.135 g THF (solvent) Sigma-Aldrich — — — — 75 mL H₂O(co-solvent) Sigma-Aldrich — — — — 25 mL Sodium 6-(2-((N-cyclopropyl-4-Product 469.50 — (1.0) (25.78) (12.10 g) (furan-2-yl)benzamido)methyl)phenoxy) hexanoate

6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido) methyl)phenoxy)hexanoicacid was dissolved in 75 mL of THF and cooled to 0° C. NaOH (1.135 g)was dissolved in 25 mL water, and added dropwise to the stirring THFsolution. After the addition was complete the reaction color was verydark (grayish-black), the ice bath was removed and the reaction asallowed to warm to room temperature and continue to stir an additional 2hours. The crude reaction mixture was then concentrated and the waterwas azeotroped away by charging the flask with about 100 mL portions ofMeCN (20 times). The solution salt still was not crashing out orprecipitating, so the crude salt was places on high vacuum overnight. Awhite crystalline solid appeared, and was triturated with fresh portionsof MeCN, filtered and dried overnight once again to yield a 10.0 gportion (excluding additional material for secondary crystallizationfrom the mother liquor). Theoretical yield=12.1 g (25.78 mmol). Observedyield=10.0 g, (10.0 g/12.1 g x 100)=82.6%. NMR (¹H, ¹³C, COSY) and LCMS(ESI+/−) conform to structure.

TABLE 1 MW MW EC₅₀ ID Formula Calc. Obser. nM Structure 1 C₂₉H₃₃NO₄459.58 458.2 [M − H]− 42

2 C₃₀H₃₉BrN₂O₅ 587.55 587.2/ 589.2 [M + H]+

3 C₃₆H₄₄N₂O₅ 584.74 585.3 [M + H]+

4 C₃₂H₃₆N₂O₅ 528.64 529.3 [M + H]+

5 C₃₄H₄₀N₂O₅ 556.69 555.3 [M − H]−

6 C₃₀H₃₂N₂O₅ 500.59 499.2 [M − H]−

7 C₃₀H₃₃N₃O₅ 515.6 514.2 [M − H]−

8 C₂₉H₃₁NO₄ 457.56 456.2 [M − H]− 115

9 C₂₈H₃₀N₂O₄ 458.55 457.2 [M − H]− 1960

10 C₂₈H₃₀N₂O₄ 458.55 457.2 [M − H]−

11 C₂₆H₂₉N₃O₄ 447.53 446.2 [M − H]− 2120

12 C₂₇H₂₉NO₅ 447.52 446.2 [M − H]− 19.6

13 C₂₇H₂₉NO₅ 447.52 446.2 [M − H]− 215

14 C₂₇H₂₉NO₄S 463.59 462.2 [M − H]− 1800

15 C₂₇H₂₉NO₄S 463.59 462.2 [M − H]− 58.4

16 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]−

17 C₃₂H₃₂N₂O₄ 508.61 507.2 [M − H]−

18 C₃₂H₃₂N₂O₄ 508.61 507.2 [M − H]−

19 C₃₀H₃₁N₃O₄ 497.58 496.2 [M − H]−

20 C₃₁H₃₁NO₅ 497.58 496.2 [M − H]−

21 C₃₁H₃₁NO₅ 497.58 496.2 [M − H]−

22 C₃₁H₃₁NO₄S 513.65 512.2 [M − H]−

23 C₃₁H₃₁NO₄S 513.65 512.2 [M − H]−

24 C₃₃H₃₄N₂O₄ 522.63 521.2 [M − H]−

25 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

26 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

27 C₃₀H₃₂N₄O₄ 512.6 511.2 [M − H]−

28 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

29 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

30 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

31 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

32 C₂₄H₃₀BrNO₄ 476.4 476.1/ 474.1 [M − H]− 611

33 C₃₀H₃₅NO₄ 473.6 472.3 [M − H]− 954

34 C₂₉H₃₄N₂O₄ 474.59 473.2 [M − H]− 5140

35 C₂₉H₃₄N₂O₄ 474.59 473.2 [M − H]− 6400

36 C₂₇H₃₃N₃O₄ 463.57 462.2 [M − H]− 15400

37 C₂₈H₃₃NO₅ 463.57 462.2 [M − H]− 41

38 C₂₈H₃₃NO₅ 463.57 462.2 [M − H]− 290

39 C₂₈H₃₃NO₄S 479.63 478.2 [M − H]− 2100

40 C₂₈H₃₃NO₄S 479.63 478.2 [M − H]− 179

41 C₃₃H₄₀N₂O₅ 544.68 543.3 [M − H]−

42 C₃₂H₃₉N₃O₅ 545.67 544.3 [M − H]−

43 C₃₂H₃₉N₃O₅ 545.67 544.3 [M − H]−

44 C₃₀H₃₈N₄O₅ 534.65 533.3 [M − H]−

45 C₃₁H₃₈N₂O₆ 534.64 533.3 [M − H]−

46 C₃₁H₃₈N₂O₆ 534.64 533.3 [M − H]−

47 C₃₁H₃₈N₂O₅S 550.71 549.2 [M − H]−

48 C₃₁H₃₈N₂O₅S 550.71 549.2 [M − H]−

49 C₃₃H₃₄N₂O₄ 522.63 521.2 [M − H]−

50 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

51 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

52 C₃₀H₃₂N₄O₄ 512.6 511.2 [M − H]−

53 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

54 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

55 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

56 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

57 C₂₉H₃₃NO₄ 459.58 458.2 [M − H]− 60

58 C₂₈H₃₂N₂O₄ 460.56 459.2 [M − H]− 1240

59 C₂₈H₃₂N₂O₄ 460.56 459.2 [M − H]− 2860

60 C₂₆H₃₁N₃O₄ 449.54 448.2 [M − H]− 710

61 C₂₇H₃₁NO₅ 449.54 448.2 [M − H]− 9.0

62 C₂₇H₃₁NO₅ 449.54 448.2 [M − H]− 61

63 C₂₇H₃₁NO₄S 465.6 464.2 [M − H]− ND

64 C₂₇H₃₁NO₄S 465.6 464.2 [M − H]− 17.2

65 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− 405

66 C₃₀H₃₄N₂O₄ 486.6 485.2 [M − H]− 786

67 C₃₀H₃₄N₂O₄ 486.6 485.2 [M − H]− 1490

68 C₂₈H₃₃N₃O₄ 475.58 474.2 [M − H]− 605

69 C₂₉H₃₃NO₅ 475.58 474.2 [M − H]− 51.4

70 C₂₉H₃₃NO₅ 475.58 474.2 [M − H]− 127

71 C₂₉H₃₃NO₄S 491.64 490.2 [M − H]− 753

72 C₂₉H₃₃NO₄S 491.64 490.2 [M − H]− 29.3

73 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]− ND

74 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]− ND

75 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]− 1190

76 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]− 318

77 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]− 372

78 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]− 1870

79 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]− 301

80 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]− 439

81 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]− 597

82 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]− 150

83 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]− 364

84 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− 2500

85 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− ND

86 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− 1300

87 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− 1150

88 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− ND

89 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− 1760

90 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]− 1300

91 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]− 1150

92 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]− 1760

93 C₃₂H₃₇NO₄ 499.64 498.3 [M − H]− 1340

94 C₃₃H₃₉NO₄ 513.67 512.3 [M − H]− ND

95 C₃₅H₃₅NO₄ 533.66 532.3 [M − H]− ND

Example 1: Synthesis of6-(2-((6-(Furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl 6-(2-formylphenoxy)hexanoate

A solution of salicylaldehyde (5.0 g, 40.9 mmol) in DMF (50 mL) wastreated with potassium carbonate (8.48 g, 61 mmol) and ethyl-6-bromohexanoate (10.96 g, 49.4 mmol) at rt under nitrogen atmosphere. Theresulting reaction mixture was heated at 80° C. with constant stirringfor 3 h. The reaction mixture was cooled to rt and filtered and washedwith ethyl acetate. The filtrate was concentrated under reduced pressureand residue obtained was diluted with cold water (50 mL), beforeextracting with ethyl acetate (200 mL). The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution, 10% EtOAc-hexanes) to afford the title compound(10.01 g, 93.4% yield). LCMS (m/z): 265.5 (M+1)⁺.

b) Synthesis of ethyl 6-(2-((isopropylamino)methyl)phenoxy)hexanoate

In a 100-mL round bottom flask, isopropyl amine (2.70 g, 45.7 mmol) andethyl 6-(2-formylphenoxy)hexanoate (10 g, 37.8 mmol) were dissolved in1,2-dichloroethane (50 mL) at rt. AcOH (14.8 mL) was added carefully tothe above mixture (exothermic) followed by portion wise addition ofsodium triacetoxyborohydride (17.8 g, 83.9 mmol) at rt. The reactionmixture was stirred at rt under nitrogen atmosphere for 4 h. Thereaction mixture was quenched by adding saturated sodium carbonatesolution, and was extracted with ethyl acetate. The ethyl acetateextract was washed with brine and dried over anhydrous Na₂SO₄. Thesolution was concentrated under reduced pressure to give title compound(11.1 g, 94%). LCMS (m/z): 308.5 (M+1)⁺.

c) Synthesis of ethyl6-(2-((6-chloro-N-isopropylnicotinamido)methyl)phenoxy) hexanoate

In a 50-mL round bottom flask, EDCI.HCl (0.746 g, 3.89 mmol) and DIPEA(1.3 mL, 7.46 mmol) were added to a solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (1.0 g, 3.25 mmol),6-chloronicotinic acid (0.612 g, 3.9 mmol) and HOBt (0.598 g, 3.9 mmol)in dimethylformamide (10 mL) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The reaction mixture was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (eluting with10% EtOAc-hexanes) to furnish the title compound (1.2 g, 75.4%). LCMS(m/z): 469.1 (M+Na)⁺.

d) Synthesis of ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy) hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((6-chloro-N-sopropylnicotinamido)methyl)phenoxy)hexanoate (1.2 g,2.69 mmol), furan-2-ylboronic acid (0.328 g, 2.93 mmol) and Na₂CO₃(0.647 g, 6.10 mmol) in DME-water (9:1, 10 mL) was degassed by purgingargon gas at rt. Pd(dppf)Cl₂′DCM (0.099 g, 0.121 mmol) was added to theabove mixture under nitrogen atmosphere at rt. The resulting mixture wasrefluxed for 4 h under nitrogen atmosphere. The reaction mixture wascooled to room temperature and filtered through a celite bed and washedwith ethyl acetate. The combined filtrate was concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (gradient elution with 10-25% EtOAc-hexanes) to affordtitle compound (609 mg 47.3%). LCMS (m/z): 479 (M+1)⁺.

e) Synthesis of6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy) hexanoicacid

25-mL round bottom flask, ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoate(0.601 g, 1.25 mmol) was dissolved in THF (4 mL)-water (2 L)-methanol (1mL) at room temperature. Lithium hydroxide monohydrate (0.131 g, 3.14mmol) was added to the solution at and reaction mixture was stirred atrt for 3 h. The reaction mixture was concentrated under reduced pressureand residue obtained was dissolved in water and washed with diethylether. The aqueous phase was then acidified (HCl) and extracted withethyl acetate (30 mL×3). The combined extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography togive title compound (0.502 g, 89.2%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 11.78 (s, 1H), 8.61 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.84 (s, 1H),7.74 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H),7.15 (d, J=3.6 Hz, 1H), 7.00-6.88 (m, 2H), 6.73-6.60 (m, 1H), 4.54 (s,2H), 4.18 (s, 1H), 3.98 (d, J=6.6 Hz, 2H), 2.23 (t, J=7.2 Hz, 2H), 1.76(br, 2H), 1.60-1.53 (m, 2H), 1.46 (br, 2H), 1.14 (d, J=6.4 Hz, 6H).LC-MS (m/z): 473.1 (M+Na)⁺. HPLC: 96.1%. (210 nm).

Example 2: Synthesis of6-(2-((5-(Furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((5-bromo-N-isopropylpicolinamido)methyl)phenoxy)hexanoate

In 50-mL round bottom flask, EDCI.HCl (0.521 g, 2.7 mmol) and triethylamine (0.76 mL, 5.6 mmol) were sequentially added to a solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.7 g, 2.2 mmol),5-bromopicolinic acid (0.505 g, 2.5 mmol) and HOBt (0.418 g, 3.09 mmol)in dimethylformamide (7 mL) at rt under nitrogen atmosphere. Theresulting reaction mixture was stirred at for 16 h at room temperatureunder nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure and residue obtained was purified by silica gel columnchromatography and eluting with 15% EtOAc-hexanes gave title compound(0.506 g, 46.9%). LCMS (m/z): 491 (M+1)⁺.

b) Synthesis of ethyl6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl) phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred suspension of ethyl6-(2-((5-bromo-N-isopropylpicolinamido)methyl)phenoxy)hexanoate (0.500g, 1 02 mmol), furan-2-yl boronic acid (0.125 g, 1.12 mmol) and Na₂CO₃(0.27 g, 2.55 mmol) in DME-water (9:1, 10 mL) was degassed by purgingargon gas at rt. Pd(dppf)Cl₂′DCM (0.041 mg, 0.05 mmol) was added to theabove solution under nitrogen atmosphere. The resulting reaction mixturewas refluxed for 4 h under nitrogen atmosphere. The reaction mixture wascooled to room temperature, filtered, and washed with ethyl acetate. Thecombined filtrate was concentrated under reduced pressure and residueobtained was purified by silica column chromatography (gradient elution,10% to 25% EtOAc-hexanes) to afford title compound (0.230 g 48.7%yield). LCMS (m/z): 501.3 (M+Na)⁺.

c) Synthesis of6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoicacid

In a 25-mL round bottom flask, ethyl6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoate(0.22 g, 0.4 mmol) was dissolved in THF (4 mL)-H₂O (2 mL)-MeOH (1 mL) atroom temperature. Lithium hydroxide monohydrate (0.048 g, 1.1 mmol) wasadded to the solution and resulting mixture was stirred at rt for 3h.The reaction mixture was concentrated under reduced pressure and residueobtained was dissolved in water and washed with diethyl ether. Theaqueous phase was then acidified (HCl) and extracted with ethyl acetate(30 mL×3). The combined extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution with50% EtOAc-hexanes) to give title compound (0.068 g, 32.8%). ¹H NMR (400MHz, DMSO-d₆, 90° C.): δ 12.17-11.50 (br s, 1H), 8.91 (s, 1H), 8.12 (s,1H), 7.81 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.18(t, J=7.2 Hz, 1H), 7.15-7.06 (m, 1H), 6.93-6.89 (m, 2H), 6.72-6.55 (m,1H), 4.63 (s, 2H), 4.25 (br, 1H), 4.02 (br s, 2H), 2.25 (t, J=7.2 Hz,2H), 1.78 (br, 2H), 1.63-0.60 (m, 2H), 1.57-1.42 (m, 2H), 1.13 (br s,6H). LCMS (m/z): 473.1 (M+Na)⁺. HPLC=97.49% (210 nm).

Example 3: Synthesis of6-(2-((3-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((3-bromo-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example 1(0.500 g,1.62 mmol) in DMF (5 mL), was treated sequentially with 3-bromo benzoicacid (0.360 g, 1.79 mmol), EDCI.HCl (0.618 g, 3.24 mmol), HOBt (0.440 g,3.24 mmol), and triethylamine (0.68 mL, 4.8 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 4 h undernitrogen atmosphere. Upon completion of the reaction (TLC), the reactionmixture quenched with cold water and extracted with ethyl acetate (50mL×3). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (gradientelution, 10-20% EtOAc-hexanes) to afford the title compound as clear oil(406 mg, 53.5%). LCMS (m/z): 491.9 (M+Na)+.

b) Synthesis of methyl6-(2-((3-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy) hexanoate

In a resealable reaction tube, ethyl6-(2-((3-bromo-N-isopropylbenzamido)methyl) phenoxy)hexanoate (0.400 g,0.81 mmol), 2-furan boronic acid (0.113 g, 0.98 mmol) and Na₂CO₃ (1.32g, 12.45 mmol) were dissolved in DME (1.5 mL) and EtOH (1.5 mL) at rtunder nitrogen atmosphere. The solution was degassed by purging argongas at rt for 10 min. Pd(PPh₃)₃ (28.2 mg, 0.024 mmol) was added to theabove solution at rt under nitrogen. The resulting mixture was heated at90° C. for 4 h. Upon completion of the reaction (TLC), the reactionmixture was cooled to rt and diluted with cold water, before extractingwith ethyl acetate (50 mL×3). The combined organic extract was washedwith brine, dried over dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue obtained (0.4 g) was used in thenext step without further purification.

c) Synthesis of6-(2-((3-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid)

In a 25-mL round bottom flask, methyl6-(2-((3-(furan-2-yl)-N-isopropylbenzamido) methyl)phenoxy)hexanoate(0.40 g, 0.83 mmol) was dissolved in THF (10 mL)-water (3 mL)-ethanol (3mL) mixture at rt. Lithium hydroxide monohydrate (0.105 g, 2.51 mmol)was added to the above solution and the reaction mixture was stirred at50° C. for 4 h. Upon completion of the reaction (TLC), the reactionmixture was concentrated under reduced pressure. The residue obtainedwas diluted with cold water and acidified with HCl (2N), beforeextracting with ethyl acetate (50 mL×3). The combined organic extractwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford title compound (180 mg, 47.8%) asoff-white solid. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.82 (s, 1H),7.75-7.69 (m, 3H), 7.48 (br, 1H), 7.31-7.27 (m, 3H) 7.21 (t, J=7.6 Hz,1H), 6.96 (t, J=7.2 Hz, 2H), 6.66-6.54 (br, 1H), 4.53 (s, 2H), 4.25-3.89(m, 1H), 2.26-2.21 (m, 2H), 1.75 (br, 2H), 1.65-1.36 (m, 4H), 1.20-1.02(br s, 6H). LCMS (m/z): 450.4 (M+1)⁺. HPLC: 6.65% (210 nm).

Example 4: Synthesis of6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.51 g, 1.66 mmol) ofexample I(b) in DMF (5 mL), was treated sequentially with4-methylbenzoic acid (0.221 g, 1.54 mmol), HBTU (1.84 g, 4.86 mmol) andtriethylamine (0.818 g, 8.10 mmol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 18 h. Upon completion of thereaction (TLC), the reaction mixture was diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give title compound (0.450g, 65%) as a clear oil. LCMS (m/z): 426.3 (M+1)⁺.

b) Synthesis of6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-ethylbenzamido)methyl)phenoxy)hexanoate (0.400 g,0.94 mmol) was dissolved in TI-IF (2 mL)-water (1 mL) mixture at rt.Lithium hydroxide monohydrate (0.197 g, 4.7 mmol) was added to the abovesolution and the reaction mixture was stirred at it for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was washed with diethyl ether and n-pentane, solventdecanted and residue dried under reduced pressure to afford the titleproduct (0.258 g, 69%) as clear oil. ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ11.81 (s, 1H), 7.40-7.12 (m, 6H), 7.07-6.82 (m, 2H), 4.51 (s, 2H), 4.13(br, 1H), 4.01 (br t, J=6.0 Hz, 2H), 2.34 (s, 3H), 2.24 (t, J=7.2 Hz,2H), 1.78-1.74 (m, 2H), 1.63-1.57 (m, 2H), 1.49-1.47 (m, 2H), 1.08 (d,J=6.4 Hz, 6H). LCMS (m/z): 398.1 (M+1)⁺. HPLC: 96.8% (210 nm).

Example 5: Synthesis of6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example I(b) (0.500 g,1.62 mmol) in DMF (7 mL), was treated sequentially with 4-fluorobenzoicacid (0.272 g, 1.94 mmol), EDCI.HCl (0.370 g, 1.94 mmol), HOBt (0.261 g,1.94 mmol) and diisopropylethylamine (0.313 g, 2.43 mmol) at rt undernitrogen atmosphere. The reaction mixture was stirred at rt for 18 hunder nitrogen atmosphere. Upon completion of the reaction (TLC), thereaction mixture was diluted with cold water and extracted with ethylacetate (25 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution, 15% EtOAc-hexanes) to give the title compound (0.41 g, 58.8%)as clear oil. LCMS (m/z): 430.0 (M+1)⁺.

b) Synthesis of6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-fluoro-N-isopropylbenzamido)methyl) phenoxy)hexanoate (0.400 g,0.93 mmol) was dissolved in THF (2 mL)-water (1 mL) mixture at itLithium hydroxide monohydrate (0.195 g. 4.6 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution 30% EtOAc-hexanes) to give the title compound (0.110 g, 29.4%)as clear oil. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 12.08 (br s, 1H),7.49 (br, 2H), 7.26-7.18 (m, 4H), 6.96-6.91 (m, 2H), 4.50 (s, 2H), 4.10(s, 1H), 4.00 (d, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 1.86-1.68 (m,2H), 1.62-1.58 (m, 2H), 1.51-1.48 (m, 2H) 1.09 (d, J=6.4 Hz, 6H). LCMS(m/z): 402.1 (M+1)⁺. HPLC: 95.32% (210 nm).

Example 6: Synthesis of6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example I(b) (0.50 g,1.63 mmol) in DCM (9 mL)-DMF (1 mL), was treated with4-trifluoromethoxybenzoic acid (0.32 g, 1.55 mmol), HBTU (1.7 g, 4.65mmol) and triethylamine (0.7 mL, 5.0 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 3 h undernitrogen atmosphere. Upon completion of the reaction (TLC), the reactionmixture quenched with water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 10-20%EtOAc-hexanes) to afford the title compound (0.312 g, 38.6%) as a clearoil. LCMS (m/z): 496 (M+1)⁺.

b) Synthesis of6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoate (0.250 g, 0.50 mmol) was dissolved in THF (10mL), water (5 mL) and EtOH (5 mL) mixture at it Lithium hydroxidemonohydrate (0.636 mg, 1.51 mmol) was added to the above solution andthe reaction mixture was stirred at rt for 18 h. Upon completion of thereaction (TLC), the reaction mixture was concentrated under reducedpressure and the residue obtained was diluted with water. The aqueoussolution was acidified with 1N HCl and extracted with ethyl acetate (50mL×3). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution 30%EtOAc-hexanes) to give the title compound (0.230 g, 97.5%) as clear oil.¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.9 (br, 1H), 7.56 (m, 2H),7.44-7.35 (m, 2H), 7.28-7.15 (m, 2H), 7.00-6.88 (m, 2H), 4.52 (s, 2H),4.21-4.04 (m, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H),1.78-1.75 (m, 2H), 1.63-1.58 (m, 2H), 1.53-1.42 (m, 2H), 1.11 (d, J=6.4Hz, 6H). LCMS (m/z): 466.6 (M-1)⁺. HPLC: 97.89% (210 nm).

Example 7: Synthesis of6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

The title compound (0.306 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.500 g, 1.6 mmol) ofExample I(b) and 4-N,N-dimethyl amino benzoic acid (0.26 g, 1.57 mmol)following the procedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 7.32-7.25 (m, 2H), 7.24-7.14 (m, 2H), 7.00-6.87 (m, 2H), 6.71 (d,J=8.8 Hz, 2H), 4.51 (s, 2H), 4.25-4.21 (m, 1H), 4.02 (t, J=6.3 Hz, 2H),2.94 (s, 6H), 2.23 (t, J=7.2 Hz, 2H), 1.78-1.73 (m, 2H), 1.62-1.56 (m,2H), 1.53-1.42 (m, 2H), 1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 427.25(M+1)⁺. HPLC: 96.81% (210 nm).

Example 8: Synthesis of6-(2-((4-Cyano-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.070 g) was prepared from methyl6-(2-((isopropylamino) methyl)phenoxy) hexanoate (0.50 g, 1.62 mmol) ofExample I(b) and 4-cyanobenzoic acid (0.263 g, 1.79 mmol) following theprocedure of Example-6 to afford the product. ¹H NMR (400 MHz, DMSO-d6,90° C.) δ 12.0 (br s, 1H), 7.97 (d, J=7.6 Hz, 2H), 7.77 (br, 0.8H), 7.69(d, J=7.6 Hz, 2H), 7.49 (br, 0.9H), 7.24-1.18 (m, 3H), 6.99-6.91 (m,3H), 4.55 (s, 2H), 4.42-4.32 (br, 1H), 4.03 (br, 2H), 3.84 (br, 2H),2.24 (br, 2.8H), 1.79 (br, 2H), 1.65-1.41 (br, 6H), 1.33-1.17 (br,3.5H), 1.04 (d, J=6 Hz, 6H). (NMR peaks were broad due to presence ofrotamers). LCMS (m/z): 431.2 (M+Na)⁺. HPLC=99.17% (210 nm).

Example 9: Synthesis of6-(2-((N-isopropyl-4-methoxybenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.235 g) was prepared from methyl6-(2-((isopropylamino) methyl)phenoxy)hexanoate (0.500 g, 1.62 mmol) ofExample I(b) and 4-methoxybenzoic acid (0.271 g, 1.8 mmol) following theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ 11.81 (s,1H), 7.42-7.34 (m, 2H), 7.26-7.15 (m, 2H), 6.99-6.91 (m, 4H), 4.51 (s,2H), 4.17-4.14 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.80 (s, 3H), 2.24 (t,J=7.2 Hz, 2H), 1.78-1.74 (m, 2H), 1.64-1.56 (m, 2H), 1.51-1.45 (m, 2H),1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 431.2 (M+Na)⁺. HPLC: 97.61% (210nm).

Example 10: Synthesis of6-(2-((4-chloro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.275 g) was prepared from methyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.500 g, 1.62 mmol) ofexample I(b) and 4-chlorobenzoic acid (0.28 g, 1.8 mmol) following theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.47-7.45(m, 4H), 7.24-7.18 (m, 2H), 6.96-6.91 (m, 2H), 4.50 (s, 2H), 4.18-3.95(m, 3H), 2.24 (t, J=7.2 Hz, 2H), 1.77-1.72 (m, 2H), 1.64-1.47 (m, 4H),1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 440.2 (M+Na)⁺. HPLC: 97.5% (210 nm).

Example 11: Synthesis of6-(2-((4-acetyl-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.150 g) was prepared from methyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.50 g, 1.62 mmol) ofExample I(b) and 4-acetyl benzoic acid (0.32 g, 1.95 mmol) using theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.84 (s,1H), 8.07-7.95 (br, 2H), 7.56 (br, 2H), 7.30-7.18 (m, 2H), 6.95 (t,J=7.2 Hz, 2H), 4.53 (br s, 2H), 4.01 (br, 3H), 2.60 (s, 3H), 2.24 (t,J=7.2 Hz, 2H), 1.78-1.75 (m, 2H), 1.62-0.158 (m, 2H), 1.51-1.46 (m, 2H),1.01 (br s, 6H). LCMS (m/z): 426.2 (M+1)⁺. HPLC=95.21% (210 nm).

Example 12: Synthesis of6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl)phenoxy)hexanoicacid

The title compound (0.130 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.5 g, 1.62 mmol) ofexample I(b) and 4-methane sulfonyl benzoic acid (0.39 g, 1.95 mmol)following the procedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 12.03 (br s, 1H), 7.94 (br, 2H), 7.63 (br, 2H), 7.23 (d, J=7.2 Hz,1H), 7.17 (t, J=7.6 Hz, 1H), 6.91 (t, J=7.2 Hz, 2H), 4.54 (br, 2H), 4.01(br, 3H), 3.18 (s, 3H), 2.21 (t, J=7.3 Hz, 2H), 1.72 (br, 2H), 1.62-1.59(m, 2H), 1.48 (br, 2H), 1.08 (br s, 6H). LCMS (m/z): 462.2 (M+1)⁺. HPLC:98.89 (210 nm).

Example 13: Synthesis of6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((4-bromo-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.76 g, 2.48 mmol) ofexample I(b) in DMF (2 mL), was treated sequentially with 4-bromobenzoic acid (0.500 g, 2.48 mmol), HBTU (2.81 g, 7.44 mmol) andtriethylamine (0.78 g, 7.44 mmol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 3 h. Upon completion of thereaction (TLC), the reaction mixture was diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give title compound (0.660g, 54.3%) as a clear oil. LCMS (m/z): 490.1 (M+1)⁺.

b) Synthesis of ethyl6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoate

In a resealable reaction tube, the solution of ethyl6-(2-((4-bromo-N-isopropylbenzamido) methyl)phenoxy)hexanoate (0.40 g,0.81 mmol) in toluene (40 mL), was treated sequentially with pyrrolidinehydrochloride (0.115 g, 1.06 mmol), rac-BINAP (0.101 g, 0.16 mmol) andCs₂CO₃ (1.32 g, 4.05 mmol) at rt under nitrogen atmosphere. The mixturewas degassed by purging with argon gas and thereafter treated withPd₂(dba)₃ (0.134 mg, 0.14 mmol) under atmosphere. The resulting reactionmixture was heated at 70° C. for 12 h. Upon completion of the reaction(TLC), the reaction mixture was cooled to rt and diluted with cold waterbefore extracting with ethyl acetate (100 mL×3).The combined organicextract was washed with brine and concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography(gradient elution, 10-20% EtOAc-hexanes) to afford title compound (308mg, 79.2%). LCMS (m/z): 481.1 (M+1)⁺.

c) Synthesis of6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy) hexanoicacid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoate(0.30 g, 0.62 mmol) was dissolved in THF (10 mL)-water (3 mL)-EtOH (3mL) mixture at rt. Lithium hydroxide monohydrate (78.7 mg, 1.87 mmol)was added to the above solution and the reaction mixture was stirred atrt for 12 h. Upon completion of the reaction (TLC), the reaction mixturewas concentrated under reduced pressure and the residue obtained wasdiluted with water. The aqueous solution was acidified with 1N HCl andextracted with ethyl acetate (50 mL×3). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 5% MeOH—CHCl₃) to give the title compound (120mg, 42.5%) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆, 90° C.): δ 7.28(d, J=8.0 Hz, 2H), 7.25-7.15 (m, 2H), 7.01-6.87 (m, 2H), 6.54 (d, J=8.0Hz, 2H), 4.51 (s, 2H), 4.26-4.18 (m, 1H), 4.02 (t, J=6.0 Hz, 2H),3.32-3.22 (m, 4H), 2.24 (t, J=7.2 Hz, 2H), 2.03-1.92 (m, 4H), 1.78-1.74(m, 2H), 1.62-1.58 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (d, J=6.4 Hz, 6H).LCMS (m/z): 453.4 (M+1)⁺. HPLC: 97.99% (210 nm).

Example 14: Synthesis of6-(2-((4-(Cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid a) Synthesis of ethyl6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a resealable tube, ethyl6-(2-((4-bromo-N-isopropylbenzamido)methyl)phenoxy) hexanoate fromexample-13(a) (0.40 g, 0.86 mmol), cyclopropyl acetylene (0.534 g, 8.03mmol) CuI (0.015 g, 0.08 mmol), were dissolved in dry DMF (1 mL) at rtunder nitrogen atmosphere. The solution was degassed and treated withPdCl₂(PPh₃)₂ (28.5 mg, 0.04 mmol) and triethyl amine (0.24 mL, 2.4 mmol)under argon atmosphere. The resulting mixture was heated at 60° C. for24 h. Upon completion of the reaction (TLC), the reaction mixture wascooled to room temperature, diluted with cold water and extracted withEtOAc (3×50 mL). The combined organic extract was washed with brine andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography and gradient elution with 10-20%EtOAc-hexanes gave the title compound (316 mg, 77.5%). LCMS (m/z): 476.3(M+1)⁺.

b) Synthesis of6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-ml round bottom flask, ethyl6-((4(4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.250 g, 0.52 mmol) was dissolved in THF (10 mL), water (3 mL) andethanol (3 mL) mixture at rt. Lithium hydroxide monohydrate (0.066 mg,1.57 mmol) was added to the above solution and the reaction mixture wasstirred at rt for 12h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure and the residueobtained was diluted with water and acidified with 1N HCl and extractedwith ethyl acetate (50 mL×3). The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by preparative HPLC to givethe title compound (170 mg, 72.21%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 11.88 (br s, 1H), 7.38-7.34 (m, 4H), 7.27-7.15 (m, 2H), 6.99-6.87 (m,2H), 4.50 (s, 2H), 4.15-4.03 (m, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24 (t,J=7.2 Hz, 2H), 1.76-1.74 (m, 2H), 1.66-1.41 (m, 4H), 1.08 (d, J=6.4 Hz,6H), 0.93-0.86 (m, 2H), 0.81-0.69 (m, 2H). LCMS (m/z): 448.1 (M+1)⁺.HPLC: 99.49% (210 nm).

Example 15: Synthesis of6-(2-((4-Cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of methyl 4-cyclopropoxybenzoate

In a resealable reaction tube, methyl 4-hydroxybenzoate (2.0 g, 13.14mmol) and bromocyclopropane (5.26 g, 43.47 mmol) were dissolved in dryDMF (10 mL) at rt under nitrogen atmosphere. K₂CO₃ (6.0 g, 43.47 mmol)was added to the above solution and resulting reaction mixture washeated in microwave at 140° C. for 2 h. Upon completion of reaction(TLC), the reaction mixture was cooled to rt and diluted with water,before extracting diethyl ether (3×100 mL). The combined organic extractwas washed with brine and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(eluting with 0-10% EtOAc/hexanes) to afford title compound (520 mg).LCMS (m/z): 192.9 (M+1)+.

b) Synthesis of 4-cyclopropoxybenzoic acid

The stirred solution of methyl 4-cyclopropoxybenzoate (0.40 g, 2.08mmol) in THF (10 mL)-MeOH (2 mL) was treated with 1NNaOH (10 mL) at rt.The reaction mixture was stirred at rt until completion of the reaction(TLC). The reaction mixture was concentrated under reduced pressure;residue obtained was acidified with 1N HCl and extracted with EtOAc (50mL×3). The combined organic extract washed with brine and concentratedunder reduced pressure to afford title compound which was used in nextstep without any further purifications (178 mg, crude).

c) Synthesis of ethyl6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy) hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.27 g, 0.87 mmol) fromexample 1(b) in DMF (5 mL) was treated sequentially with4-cyclopropoxybenzoic acid (0.150 g, 0.87 mmol), EDCI.HCl (0.336 g, 1.75mmol), HOBt (0.239 g, 1.82 mmol), and triethylamine (0.88 mL, 2.64 mmol)at rt under nitrogen atmosphere. The reaction mixture was stirred at rtfor 12 h. Upon completion of the reaction (TLC), the reaction mixturewas diluted with cold water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 20% EtOAc-hexanes)to afford the title compound (130 mg, 31.7%) as clear oil. LCMS (m/z):468.2 (M+1)⁺.

d) Synthesis of6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, methyl6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.10 g, 0.21 mmol) was dissolved in F (3 mL)-water (1 mL)-EtOH (1 mL)mixture at rt. Lithium hydroxide monohydrate (0.027 g, 0.63 mmol) wasadded to the above solution and the reaction mixture was stirred at itfor 12 h. Upon completion of the reaction (TLC), the reaction mixturewas concentrated under reduced pressure and the residue obtained wasdiluted with water. The aqueous solution was acidified with 2N HCl andextracted with ethyl acetate (10 mL×2). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by preparative HPLCto give the title compound (56 mg, 60.6%) as off white solid. ¹H NMR(400 MHz, DMSO-d₆, 60° C.) δ 7.42-7.32 (m, 2H), 7.26-7.14 (m, 2H),7.12-7.03 (m, 2H), 7.03-6.85 (m, 2H), 4.51 (s, 2H), 4.21-4.13 (m, 1H),4.01 (t, J=6.0 Hz, 2H), 3.88-3.86 (m, 1H), 2.24 (t, J=7.2 Hz, 2H),1.79-1.74 (m, 2H), 1.62-1.58 (m, 2H), 1.49-1.45 (m, 2H), 1.09 (d, J=6.4Hz, 6H), 0.87-0.75 (m, 2H), 0.71-0.62 (m, 2H). LCMS (m/z): 440.2 (M+1)⁺.HPLC=98.85% (210 nm).

Example 16: Synthesis ofN-(2-(4-(2H-Tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

a) Synthesis of 2-((isopropylamino)methyl)phenol

Isopropyl amine (2.65 g, 44.8 mmol) and salicylaldehyde (5.0 g, 40.9mmol) were dissolved in 1,2-dichloroethane (50 mL) at rt. AcOH (16 mL)was added slowly to the above solution (exothermic). Sodiumtriacetoxyborohydride (19.0 g, 89.6 mmol) was added in portions to themixture and resulting reaction mixture was stirred at rt for 4h undernitrogen atmosphere. The reaction mixture was quenched by addingsaturated sodium carbonate solution, and extracted with ethyl acetate.The ethyl acetate extract was washed with brine and dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (6.70 g, 88.7%). LCMS (m/z): 349.9 (M+1)⁺.

b) Synthesis of 4-bromo-N-(2-hydroxybenzyl)-N-isopropylbenzamide

In 100-mL round bottom flask, EDCI.HCl (9.0 g, 47 mmol) and DIPEA (17mL, 97.6 mmol) were added sequentially to a solution of2-((isopropylamino)methyl)phenol (6.50 g, 39.3 mmol), 4-bromobenzoicacid (9.50 g, 47.3 mmol) and HOBt (7.20 g, 53.3 mmol) indimethylformamide (65 mL) at rt under nitrogen atmosphere. The resultingreaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The mixture was concentrated under reduced pressure and residue obtainedwas purified by silica gel column chromatography (elution 10%EtOAc-hexanes) to give title compound (6.08 g, 46.1%). LCMS (m/z): 336.1(M+1)⁺.

c) Synthesis of 4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide

In a 50-mL round bottom flask, a stirred suspension of4-bromo-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.70 g, 2 mmol),furan-2-boronic acid (0.269 g, 2.4 mmol) and Na₂CO₃ (0.533 g, 5 mmol) inDME (9 mL)-water (1 mL) was degassed with argon gas. Pd(dppf)Cl₂.DCM(0.082 g, 0.1 mmol) was added to the above mixture at rt under nitrogenatmosphere. The resulting reaction mixture was refluxed for 4 h undernitrogen atmosphere. The reaction mixture was cooled to rt, filtered andresidue washed with ethyl acetate. The combined filtrate wasconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (gradient elution 10-20%EtOAc-hexanes) to afford title compound (512 mg, 76.4%). LCMS (m/z):336.1 (M+1)⁺.

d) Synthesis ofN-(2-(4-cyanobutoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

In 25-mL round bottom flask, a solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.50 g, 1.49mmol) in DMF (7.5 mL) was treated with potassium carbonate (0.308 g, 2.2mmol) and 5-bromopentane nitrile (0.289 g, 1.7 mmol) at rt undernitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 h.Upon completion of the reaction (TLC), the reaction mixture was cooledto rt, filtered and washed with EtOAc. The combined filtrate wasconcentrated under reduced pressure. The residue obtained was dilutedwater (50 mL) and extracted with EtOAc (200 mL). The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 10% EtOAc-hexanes) to give title compound (0.599g, 96.7%). LCMS (m/z): 417.1 (M+1)⁺.

e) Synthesis ofN-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

In a 25-mL resealable reaction tube, a solution ofN-(2-(4-cyanobutoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide (0.50 g,1.2 mmol) in DMF (7.5 mL) was treated with NaN₃ (0.39 g, 6.0 mmol) andtriethylamine hydrochloride (0.494 g, 3.58 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred 135° C. for 24h. Uponcompletion of the reaction (TLC), the reaction mixture was cooled to rtand neutralized with saturated Na₂CO₃, before extracting with EtOAc (25mL×3). The combined organic extract was washed with water, brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (120 mg, 21.8%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.76-7.72(m, 3H), 7.47 (d, J=7.6 Hz, 2H), 7.31-7.15 (m, 2H), 7.00-6.92 (m, 3H),6.61 (br, 1H), 4.52 (s, 2H), 4.09 (d, J=37.6 Hz, 3H), 2.95 (t, J=7.2 Hz,2H), 2.00-1.71 (m, 4H), 1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 482.1(M+Na)⁺. HPLC: 99.3% (210 nm).

Example 17:5-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoic acid

a) Synthesis of ethyl5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy) pentanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.30 g, 0.895mmol) of example 16(c) in DMF (5 mL) was treated with potassiumcarbonate (0.148 g, 1.09 mmol) and ethyl 5-bromopentanoate (0.205 g,0.985 mmol) at rt under nitrogen atmosphere. The reaction mixture washeated at 90° C. for 18 h under nitrogen atmosphere. Upon completion ofthe reaction (TLC), the reaction mixture was cooled at rt, diluted withcold water and extracted with ethyl acetate (10 mL×2). The combinedorganic extract was washed with water, brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 30% EtOAc-hexanes)to give title compound (0.31 g, 74.8%) as clear oil. LCMS (m/z): 464.3(M+1)⁺.

b) Synthesis of5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoic acid

In a 25-mL round bottom flask, ethyl5-(2-((4-(furan-2-yl)-N-isopropylbenzamido) methyl)phenoxy)pentanoate(0.30 g, 0.64 mmol) was dissolved in THF (3 mL)-water (3 mL) at rtLithium hydroxide monohydrate (0.135 g, 3.23 mmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (0.111 g, 39.4%) as sticky liquid. ¹H NMR (400 MHz, DMSO-d₆,60° C.): δ 11.87 (s, 1H), 7.83-7.74 (m, 3H), 7.51 (d, J=7.6 Hz, 2H),7.33-7.20 (m, 2H), 7.06-6.93 (m, 3H), 6.65 (dd, J=3.2, 1.6 Hz, 1H), 4.58(s, 2H), 4.19 (br, 1H), 4.06 (t, J=6.0 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H),1.92-1.65 (m, 4H), 1.15 (d, J=6.4 Hz, 6H). LCMS (m/z): 436.5 (M+1)⁺.HPLC: 98.85% (210 nm).

Example 18:7-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic acid

a) Synthesis of ethyl7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy) heptanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.450 g, 1.34mmol) of example 16(c) in DMF (5 mL) at rt under reduced pressure.Potassium carbonate (0.222 g, 1.60 mmol) and ethyl 7-bromoheptanoate(0.35 g, 1.67 mmol) were added at the above solution at rt undernitrogen atmosphere. The reaction mixture was heated at 90° C. for 4h.Upon completion of the reaction (TLC), the reaction mixture was cooledto rt, diluted with cold water and extracted with ethyl acetate (30mL×2). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution 10%EtOAc-hexanes) to give title compound (0.39 g, 63%) as clear oil. LCMS(m/z): 492.1 (M+1)⁺.

b) Synthesis of7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic acid

In a 25-mL round bottom flask, methyl7-(2-((4-(furan-2-yl)-N-isopropylbenzamido) methyl)phenoxy)heptanoate(0.39 g, 0.79 mmol) was dissolved in THF (3 mL)-water (3 mL) at rt.Lithium hydroxide monohydrate (0.266 g, 6.35 mmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was washed with diethyl ether (25 mL) and acidifiedwith 1N HCl. The solid precipitated was filtered, washed with n-pentaneand dried under reduced pressure to give the title compound (0.209 g,57.1%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ 7.81-7.67 (m, 3H), 7.46 (d,J=7.6 Hz, 2H), 7.26 (d, J=7.2 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.05-6.86(m, 3H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.53 (s, 2H), 4.16 (br, 1H), 4.01(t, J=6.3 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.56-1.51(m, 2H), 1.49-1.30 (m, 4H), 1.11 (d, J=6.4 Hz, 6H). LCMS (m/z): 486.2(M+Na)⁺. HPLC: 96.32% (210 nm).

Example 19:3-(2-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoicacid

a) Synthesis of ethyl 3-(2-(benzyloxy)ethoxy)propanoate

In a 250-mL round bottom flask, a stirred solution of2-(benzyloxy)ethanol (9.0 g, 59.1 mmol) in of anhydrous THF (100 mL),was treated with ethyl propenoate (5.62 g, 49.2 mmol) and sodium metal(0.0013 g, 0.591 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 18 h. Upon completion of the reaction(TLC), the reaction mixture quenched with cold water and extracted withethyl acetate (250 mL×2). The combined organic extract was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography and eluting with 10% EtOAc-hexanes gave title compound(2.51 g, 16.8%) as a clear oil. LCMS (m/z): 253.1 (M+1)⁺.

b) Synthesis of ethyl 3-(2-hydroxyethoxy)propanoate

In a 100-mL round bottom flask, a stirred solution of ethyl3-(2-(benzyloxy) ethoxy)propanoate (2.0 g, 7.93 mmol) in 20 mL of EtOAc,was treated with palladium on carbon (10 wt %, activated carbon support,0.50 g) under nitrogen atmosphere. The stirred reaction mixture washydrogenated (balloon pressure) at rt for 4 h. Upon completion of thereaction (TLC), the reaction mixture was filtered over celite bed andwashed with ethyl acetate (25 mL×2). The combined filtrate wasconcentrated under reduced pressure to give title compound as clear oil.The crude product was taken to next step without any purification.(1.203 g). LCMS (ESI, m/z): 163.0 (M+1)⁺.

c) Synthesis of ethyl 3-(2-bromoethoxy)propanoate

In a 25-mL round bottom flask, a stirred solution of ethyl3-(2-hydroxyethoxy)propanoate (0.20 g, 1.23 mmol) in of dry THF (5 mL)was treated sequentially with triphenylphosphine (0.386 g, 1.47 mmol)and carbon tetrabromide (0.614 g, 1.85 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 3 h. Uponcompletion of the reaction (TLC), the reaction mixture quenched withcold water and extracted with ethyl acetate (10 mL×2). The combinedorganic extract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution 10% EtOAc-hexanes) toafford the title product as clear oil. (0.150 g, 54.1%). LCMS (m/z):226.9 (M+2)⁺.

d) Synthesis of ethyl3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.50 g, 1.49mmol) of Example 16c in DMF (5 mL) was treated with potassium carbonate(0.247 g, 1.78 mmol) and ethyl 3-(2-bromoethoxy)propanoate (0.369 g,1.63 mmol) at rt under nitrogen atmosphere. The reaction mixture washeated at 90° C. for 18h. Upon completion of the reaction (TLC), thereaction mass cooled to rt, diluted with cold water and extracted withethyl acetate (10 mL×2). The combined organic extract was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to afford the title compound(0.421 g, 59%) as a clear oil. LCMS (m/z): 480 (M+1)⁺.

e) Synthesis of3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoic acid

In a 25-mL round bottom flask, ethyl3-(2-((4(4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoate(0.40 g, 0.83 mmol) was dissolved in THF (4 mL)-water (4 mL) at rt.Lithium hydroxide monohydrate (0.174 g, 4.1 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (0.099 g, 26.5%) as pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆, 60° C.): δ 7.80-7.78 (m, 3H), 7.52 (d, J=8.0 Hz, 2H), 7.36-7.18(m, 2H), 7.08-6.93 (m, 3H), 6.65 (t, J=2.4 Hz, 1H), 4.59 (s, 2H), 4.16(br, 3H), 3.74 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), 1.14 (d, J=6.4 Hz, 6H).LCMS (m/z): 452.3 (M+1)⁺. HPLC: 96.88% (210 nm).

Example 20:2-(3-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)aceticacid

a) Synthesis of ethyl 2-(3-hydroxypropoxy) acetate

In a 50-mL round bottom flask, a stirred solution of ethyl 3-diazo-2-oxoproponoate (1.08 ml, 7.77 mmol) was treated with catalytic amount ofrhodium diacetate (0.02 g) under nitrogen atmosphere. The reactionmixture was cooled to 0° C. and propane-1,3-diol (10 mL) was added dropwise at the same temperature. The reaction mixture was stirred at rt for3 days. Upon completion of the reaction (TLC), the reaction mixturequenched with water and extracted with ethyl acetate (100 mL×2). Thecombined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography and eluting with 50%EtOAc-hexanes afforded the title product (1.10 g, 88%) as clear oil.LCMS (m/z): 163.2 (M+1)⁺.

b) Synthesis of ethyl 2-(3-bromopropoxy) acetate

In a 50-mL round bottom flask, a stirred solution of ethyl2-(3-hydroxypropoxy)acetate (1.0 g, 6.17 mmol) in THF (20 mL) wastreated with PPh₃ (1.93 g, 7.40 mmol) and CBr₄ (3.0 g, 9.25 mmol) at rtunder nitrogen atmosphere. The reaction mixture was stirred at rt for 3hunder nitrogen atmosphere. Upon completion of the reaction (TLC), thereaction mixture was quenched with cold water and extracted with ethylacetate (100 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution with 10% EtOAc-hexanes) to afford the title product as clearoil (0.688 g, 50%). LCMS (m/z): 224 (M+1)⁺.

c) Synthesis of ethyl2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetate

A solution of 4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide(0.30 g, 0.88 mmol) of example 16c in DMF (5 mL) was treated withpotassium carbonate (0.183 g, 1.3 mmol) and ethyl2-(3-bromopropoxy)acetate (0.22 g, 0.98 mmol) at rt under nitrogenatmosphere. The reaction mixture was heated at 80° C. for 3h. Uponcompletion of the reaction (TLC), the reaction mixture was filtered andwashed with EtOAc. The combined filtrate was concentrated under reducedpressure. The residue obtained was diluted with cold water (50 mL) andextracted with EtOAc (200 mL). The organic extract was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to give the title compound(0.295 g, 70%). LCMS (m/z): 480.3 (M+1)⁺.

d) Synthesis of2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetic acid

In a 50-mL round bottom flask, ethyl2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetate (0.47 g, 0.98 mmol) was dissolved in THF(5 mL)-water (3 mL) at rt. Lithium hydroxide monohydrate (0.206 g, 4.9mmol) was added to the above solution and the reaction mixture wasstirred at rt for 18 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure and the residueobtained was diluted with cold water and washed with diethyl ether. Theaqueous solution was acidified with 2N HCl and extracted with ethylacetate (20 mL×3). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution 100% EtOAc) to give the title compound (0.205 g, 46.4%). ¹H NMR(400 MHz, DMSO-d6, 60° C.) δ 12.2 (br s, 1H), 7.75-7.73 (m, 3H), 7.48(d, J=8.0 Hz, 2H), 6.99-6.95 (m, 3H), 6.61-6.60 (m, 1H), 4.53 (s, 2H),4.12-4.08 (m, 3H), 4.0 (s, 2H), 3.68 3.61 (m, 2H), 2.05-1.94 (m, 2H),1.1 (m, J=6.4 Hz, 6H). LCMS (m/z): 452.2 (M+1)⁺. HPLC=96.27% (210 nm).

Example 21:6-(2-((4-(Furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of 4-(furan-2-yl)benzoic acid

In a 100-mL resealable reaction tube, 4-iodobenzoic acid (10.0 g, 40.03mmol) and furan-2-ylboronic acid (8.95 g, 80.06 mmol) were dissolved indegassed DMF (250 mL) and water (50 mL) at rt under nitrogen atmosphere.Pd(PPh₃)₄ (4.65 g, 3.99 mmol), K₂CO₃ (16.6 g, 120.09 mmol) weresequentially added to the above solution under nitrogen atmosphere. Theresulting mixture was degassed by purging argon gas for 15 min, andreaction mixture was heated to 90° C. until completion of the reaction(TLC). The reaction mixture was cooled to rt, diluted with cold waterand washed with ethyl acetate (3×30 mL).The aqueous layer was separatedand acidified to pH 3 with concentrated HCl, before extracting withEtOAc (100 mL×2). The combined extract was washed with brine andconcentrated under reduced pressure to get title compound (6.92 g, 92%)as light yellow solid. LCMS (m/z): 187 (M-1)⁺.

b) Synthesis of ethyl 6-(2-(((2-methoxyethyl) amino)methyl)phenoxy)hexanoate

In a 100-mL round bottom flask, 2-methoxyethanamine (0.62 g, 8.3 mmol)was added to solution of ethyl 6-(2-formylphenoxy)hexanoate (2.0 g, 7.5mmol) of example 1(a) in 1,2-dichloroethane (30 mL) at rt under nitrogenatmosphere. AcOH (3 mL) was added dropwise to the above solution at rt(exothermic). The reaction mixture was stirred at rt for 2 h undernitrogen atmosphere. Sodium borohydride (0.54 g, 14.6 mmol) was added inportions to the above reaction mixture at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for further 1 h under nitrogenatmosphere. The reaction mixture was quenched by addition of saturatedsodium carbonate solution and extracted with dichloromethane. Thedichloromethane layer was washed with brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure to give thetitle compound (2.58 g) which was used in the next step without furtherpurification. LCMS (m/z): 324.2 (M+1)⁺.

c) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-(((2-methoxyethyl)amino)methyl)phenoxy)hexanoate (0.50 g, 1.47mmol) in DMF (10 mL) was treated sequentially with 4-(furan-2-yl)benzoicacid (0.304 g, 1.62 mmol) EDCI.HCl (0.330 g, 1.56 mmol) Et₃N (0.3 mL,2.15 mmol) and HOBt (0.231 g, 1.7 mmol) at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for 16 h under nitrogenatmosphere. Upon completion of the reaction (TLC), the reaction mixturewas diluted with cold water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 50% EtOAc-hexanes)to afford the title compound (0.646 g, 89.2%) as clear oil. LCMS (m/z):494.3 (M+1)⁺.

d) Synthesis of6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoate (0.50 g, 1.01 mmol) was dissolved inTHF (5 mL)-water (3 mL) at Lithium hydroxide monohydrate (0.212 g, 5.0mmol) was added to the above solution and the reaction mixture wasstirred at rt for 12 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure and the residueobtained was diluted with water. The aqueous solution washed withdiethyl ether and acidified with 2N HCl. The solid precipitated wasfiltered, washed with n-pentane and dried under reduced pressure to givetitle compound (0.179 g, 38.13%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ12.06-11.32 (br, 1H), 7.81-7.67 (m, 3H), 7.45 (d, J=8.0 Hz, 2H),7.27-7.23 (m, 2H), 7.06-6.89 (m, 3H), 6.60 (dd, J=3.6, 2.0 Hz, 1H), 4.63(br s, 2H), 3.98 (br, 2H), 3.46 (s, 3H), 2.21 (t, J=7.2 Hz, 2H), 1.71(br, 2H), 1.56 (m, 2H), 1.42 (br, 2H). LCMS (m/z): 466.1 (M+1)⁺. HPLC:97.81% (210 nm).

Example 22:6-((3-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid

a) Synthesis of ethyl 6-((3-formylpyridin-2-yl)oxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of2-hydroxynicotinaldehyde (1.5 g, 12.19 mmol) in DMF (30 mL), was treatedwith potassium carbonate (5.0 g, 36.58 mmol) and ethyl 6-bromohexanoate(2.99 g, 13.41 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 4 h. Upon completion of the reaction(TLC), the reaction mixture was diluted with cold water and extractedwith ethyl acetate (50 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 10% EtOAc-hexanes) to give title compound (0.297g, 9.2%) as the clear oil. ¹H NMR (300 MHz, CDCl₃): δ 10.38 (s, 1H),8.36-8.34 (m, 1H), 8.09 (dd, J=7.5, 2.1 Hz, 1H), 7.00-6.96 (m, 1H), 4.44(t, J=13.2, 6.6 Hz, 2H), 4.17-4.08 (m, 2H), 2.35 (t, J=13.2, 7.2 Hz,2H), 1.90-1.85 (m, 2H) 1.77-1.65 (m, 2H), 1.56-1.46 (m, 2H), 1.24 (t,J=7.2 Hz, 3H). LCMS (m/z): Desired mass peak not observed.

b) Synthesis of ethyl6-((3-((isopropylamino)methyl)pyridin-2-yl)oxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-((3-formylpyridin-2-yl)oxy)hexanoate (300 mg, 1.13 mmol) in ethanol(10 mL) was treated with isopropyl amine (200 mg, 3.39 mmol) and aceticacid (0.3 mL) at rt under nitrogen atmosphere. The mixture stirred at rtfor 6 h under nitrogen atmosphere. Sodium borohydride (85.4 mg, 2.26mmol) was added to the above reaction mixture at rt under nitrogenatmosphere. The resulting mixture was stirred for further 3 h at rt.Upon completion of the reaction (TLC) the reaction mixture was quenchedwith saturated NaHCO₃ and extracted with ethyl acetate (50 mL×2). Thecombined organic extract was washed with water, brine, dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureto afford the title compound (310 mg) as yellow oil. The product wasused directly in the next step without any further purification. LCMS(m/z): 309.2 (M+1)⁺.

c) Synthesis of ethyl6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-((3-((isopropylamino)methyl)pyridin-2-yl)oxy)hexanoate (0.301 g, 0.974mmol) in DMF (10 mL) was treated with 4-(furan-2-yl)benzoic acid (0.210g, 1.07 mmol), EDCI.HCl (0.372 g, 1.94 mmol), HOBt (0.264 g, 1.94 mmol)and triethylamine (0.412 g, 4.07 mmol) at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for 2 days. Upon completion ofthe reaction (TLC), the reaction mixture diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to give title compound (0.251g, 53.9%) as off-white solid. LCMS (m/z): 479.2 (M+1)⁺.

d) Synthesis of6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid

In a 25-mL round bottom flask, ethyl6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoate (250 mg, 0.523 mmol) was dissolved inTHF (10 mL)-water (10 mL) mixture at it Lithium hydroxide monohydrate(109 mg. 2.61 mmol) was added to the above solution and the reactionmixture was stirred at rt for 18 h. Upon completion of the reaction(TLC), the reaction mixture was concentrated under reduced pressure. Theresidue obtained was diluted with cold water and acidified with 2N HCl,before extracting with ethyl acetate (10 mL×2). The combined organicextract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution, 50% EtOAc-hexanes) to givetitle compound (129 mg, 55%) a pale yellow gummy liquid. ¹H NMR (400MHz, DMSO-d₆, 60° C.) δ 12.02 (s, 1H), 8.08-7.96 (m, 1H), 7.80 (br, 2H),7.60-7.50 (m, 3H), 7.06 (br, 1H), 6.98 (dd, J=7.2, 5.2 Hz, 1H),6.69-6.57 (m, 1H), 4.44 (s, 2H), 4.33 (m, 2H), 4.05 (br, 1H), 2.25 (brs, 2H), 1.79-1.76 (m, 2H), 1.60-1.55 (m, 2H), 1.49-1.45 (m, 2H), 1.08(br s, 6H). LCMS (m/z): 451.2 (M+1)⁺. HPLC: 96.87% (210 nm).

Example 23:6-(2-((4-(Furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((4-bromo-N-isopropylphenylsulfonamido)methyl)phenoxy) hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (500 mg, 1.62 mmol) inpyridine (10 mL) was treated with 4-bromobenzene-1-sulfonyl chloride(496 mg, 1.95 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 12 h. Upon completion of the reaction(TLC) the reaction mixture was quenched with cold water and extractedwith ethyl acetate (25 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel (60-120 mesh)column chromatography (elution 20% EtOAc-hexanes) to give title compound(301 mg, 35%) as yellow oil. LCMS (m/z): 547.9 (M+Na)⁺.

b) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoate

In a 50-mL resealable reaction tube, ethyl6-(2-((4-bromo-N-isopropylphenylsulfonamido)methyl) phenoxy)hexanoate(300 mg, 0.57 mmol) was dissolved in degassed solvent mixture of DME (7mL), water (7 mL) and ethanol (2 mL) at rt under nitrogen atmosphere.Pd(PPh₃)₄ (19.7 mg, 0.017 mmol), furan-2-ylboronic acid (127 mg, 1.14mmol) and Na₂CO₃ (181 mg, 1.71 mmol) were sequentially added to theabove solution under nitrogen atmosphere. The resulting mixture wasdegassed by purging argon gas for 15 min. The reaction mixture washeated to 90° C. and stirred at same temperature until completion of thereaction (TLC). The reaction mixture was cooled to rt, diluted with coldwater and extracted with ethyl acetate (30 mL×3). The combined EtOAcextract was washed with brine and concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography(elution 30% EtOAc-hexanes) to afford the title product (278 mg, 95%) asclear oil. LCMS (m/z): 514.3 (M+1)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoate (270 mg, 0.526 mmol) was dissolvedin THF (10 mL), water (10 mL) and ethanol (2 mL) mixture at it. Lithiumhydroxide monohydrate (122 mg, 2.92 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 12 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and residue obtained was diluted with cold water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was washed with n-pentane to afford the title compound(186 mg, 70.1%) as off white solid. ¹H NMR (300 MHz, DMSO-d₆, 60° C.): δ11.98 (s, 1H), 8.10-7.73 (m, 5H), 7.55-7.32 (m, 1H), 7.32-7.10 (m, 2H),7.01-6.84 (m, 2H), 6.66 (dd, J=3.6, 1.8 Hz, 1H), 4.33 (s, 2H), 4.12-4.05(m, 1H), 3.97 (t, J=6.4 Hz, 2H), 2.19 (t, J=7.2 Hz, 2H), 1.74-1.70 (m,2H), 1.53-1.51 (m, 2H), 1.43-1.41 (m, 2H), 0.83 (d, J=6.6 Hz, 6H). LCMS(m/z): 508.5 (M+1)⁺. HPLC: 94.32% (210 nm).

Example 24: 6-(2-((4-(Furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of (E)-methyl 6-(2-((hydroxyimino) methyl) phenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of ethyl6-(2-formylphenoxy)hexanoate (2.0 g, 7.5 mmol) in water (40 mL), wastreated aqueous hydroxyl amine (1.25 g, 37.8 mmol) at rt. The resultingmixture was heated at 100° C. for 30 min to give an off whitesuspension. The suspension was allowed to cool to ambient temperatureand then further cooled in an ice-bath. The solid formed was filtered,washed with water and dried under reduced pressure to afford the titlecompound (1.81 g, 86.8%) as white solid. ¹H-NMR (300 MHz, DMSO-d₆): δ11.18 (s, 1H), 8.27 (s, 1H), 7.65-7.59 (m, 1H), 7.35-7.29 (m, 1H),7.04-7.00 (d, J=8.1 Hz, 1H), 6.94-6.89 (t, J=7.8 Hz, 1H), 4.06-3.96 (m,4H), 2.31-2.27 (t, J=14.4 Hz, 2H), 1.76-1.67 (m, 2H), 1.62-1.52 (m, 2H),1.46-1.38 (m, 2H), 1.17 (t, J=7.2 Hz, 3H). LCMS (m/z): 279.3 (M+1)⁺.

b) Synthesis of ethyl 6-(2-(aminomethyl)phenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of (E)-methyl6-(2-((hydroxyimino)methyl)phenoxy)hexanoate (1.30 g, 4.6 mmol) inethanol (20 mL) was treated with 10% palladium on activated carbon (0.30g) at rt under nitrogen atmosphere. The resulting suspension washydrogenated (balloon) at rt for 12 h. Upon completion of the reaction(TLC), reaction mixture was filtered over a celite bed and filtrated wasconcentrated under reduced pressure to afford the title compound (1.10g, 89.43%) as clear oil. LCMS (m/z): 266.3 (M+1)⁺.

c) Synthesis of ethyl6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, EDCI.HCl (0.25 g, 1.3 mmol) andtriethylamine (2.0 mL, 1.6 mmol) were sequentially to a solution ofmethyl 6-(2-(amino methyl)phenoxy)hexanoate (0.3 g, 1.1 mmol),4-(furan-2-yl)benzoic acid (0.21 g, 1.1 mmol) and HOBt (0.180 g, 1.3mmol) in dimethylformamide (10 mL) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The reaction mixture was concentrated under reduced pressure. Theresidue obtained was purified by silica gel (60-120 mesh) columnchromatography (elution 50% EtOAc-hexanes) to give the title compound(0.243 g, 50.7%). LCMS (m/z): 458.2 (M+Na)⁺.

d) Synthesis of 6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid

A solution of ethyl 6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate (0.25 g, 0.57 mmol) in THF (10 mL)and water (5 mL) was treated with lithium hydroxide monohydrate (0.241g, 5.7 mmol) at rt. The reaction mixture was stirred at rt for 12h Uponcompletion of reaction (TLC), the reaction mixture was concentratedunder reduced pressure and residue obtained was diluted with water. Theaqueous solution was washed with diethyl ether and acidified with 1NHCl, when solid precipitated. The solid was filtered, washed with water,n-pentane and dried under reduced pressure to afford the title compound(0.099 g, 42.7%). ¹H NMR (300 MHz, DMSO-d₆, 60° C.): δ 11.99 (s, 1H),8.83 (t, J=5.8 Hz, 1H), 8.03-7.87 (m, 2H), 7.86-7.71 (m, 3H), 7.24-7.11(m, 2H), 7.09 (d, J=3.4 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.4Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 3.99 (t,J=6.2 Hz, 2H), 2.21 (t, J=7.1 Hz, 2H), 1.76-1.71 (m, 2H), 1.57-1.44 (m,4H). LCMS (m/z): 430.1 (M+Na)⁺. HPLC: 95.46% (210 nm).

Example 25:6-(4-Bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl 6-(4-bromo-2-formylphenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of substituted5-bromo-2-hydroxybenzaldehyde (5.0 g, 24.8 mmol) in DMF (30 mL), wastreated with potassium carbonate (10.26 g, 74.4 mmol) and ethyl6-bromohexanoate (6.6 g, 29.8 mmol) at rt under nitrogen atmosphere. Thereaction mixture was heated at 90° C. for 4 h. Upon completion of thereaction (TLC) the reaction mixture was cooled to rt, diluted with coldwater and extracted ethyl acetate (250 mL×2). The combined organicextract was washed with brine and dried over anhydrous Na₂SO₄. Thesolution was concentrated under reduced pressure to give the titlecompound (7.97 g, 94%) as yellow oil. LCMS (m/z): 343.2 (M+1)⁺.

b) Synthesis of ethyl 6-(2-(aminomethyl)-4-bromophenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of substituted ethyl6-(4-bromo-2-formylphenoxy)hexanoate (2.0 g, 5.84 mmol) in1,2-dichloroethane (50 mL), was treated with isopropylamine (0.37 g,6.26 mmol) and acetic acid (2.5 g, 41.6 mmol) at rt. The mixture wasstirred at rt for 30 min and treated with NaBH(OAc)₃ (2.70 g, 12.73mmol) at rt under nitrogen atmosphere. The reaction mixture was stirredat rt for 3 h. Upon completion of the reaction (TLC) the reactionmixture was quenched with saturated NaHCO₃ and extracted with ethylacetate (50 mL×2). The combined organic extract was washed with water,brine and dried over anhydrous Na₂SO₄. The solution was concentratedunder reduced pressure to afford the title compound (1.52 g) as yellowoil, which was used in the next step without further purification. LCMS(m/z): 386.1 (M+1)⁺.

c) Synthesis of ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of6-(4-bromo-2-((isopropylamino)methyl)phenoxy)hexanoate (500 mg, 1.29mmol) in DMF (15 mL), was treated sequentially with4-(furan-2-yl)benzoic acid (267 mg, 1.42 mmol), EDCI.HCl (492 mg, 2.58mmol), HOBt (350 mg, 2.58 mmol) and triethylamine (546 mg, 5.6 mmol) atrt under nitrogen atmosphere. The reaction mixture was stirred at rt for18 h under nitrogen atmosphere. Upon completion of the reaction (TLC),the reaction mixture was diluted with cold water and extracted withethyl acetate (25 mL×2). The combined organic extract was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give the title compound(681 mg, 94.7%) as clear oil. LCMS (m/z): 557.2 (M+1)⁺.

d) Synthesis of6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, a stirred solution ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(500 mg, 0.899 mmol) was dissolved in THF (10 mL)-water (10 mL)-EtOH (2mL) at rt. Lithium hydroxide monohydrate (188 mg, 4.48 mmol) was addedto the above solution and the reaction mixture was stirred at n for 5 h.Upon completion of the reaction (TLC), the reaction mixture wasconcentrated under reduced pressure and the residue obtained was dilutedwith water. The aqueous solution was acidified with 2N HCl and extractedwith ethyl acetate (10 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was washed repeatedly with n-pentane togive the title compound (349 mg, 73.7%) as clear oil. ¹H NMR (400 MHz,DMSO-d₆, 60° C.): δ 11.80 (s, 1H), 7.81-7.75 (m, 3H), 7.44 (d, J=7.6 Hz,2H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 7.31 (s, 1H), 7.00 (d, J=3.2 Hz, 1H),6.95 (d, J=8.8 Hz, 1H), 6.66-6.58 (m, 1H), 4.51 (s, 2H), 4.17 (br, 1H),4.02 (t, J=6.4 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H),1.79-1.75 (m, 4H), 1.61-1.58 (m, 2H), 1.52-1.40 (m, 2H), 1.11 (d, J=6.4Hz, 6H). LCMS (m/z): 527.9 (M+1)⁺. HPLC: 95.01% (210 nm).

Example 26:6-(4-Fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

The title compound (190 mg) was prepared starting from5-fluoro-2-hydroxybenzaldehyde (1.0 g, 7.14 mmol) using the procedure ofExample-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.77-7.74 (m, 3H), 7.48(d, J=7.6 Hz, 2H), 7.01-6.99 (m, 4H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.52(s, 2H), 4.15 (br, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H),1.81-1.70 (m, 2H), 1.62-1.58 (m, 2H), 1.49-1.47 (m, 2H), 1.11 (d, J=6.6Hz, 6H). LCMS (m/z): 468.2 (M+1)⁺. HPLC: 96.75% (210 nm).

Example 27:6-((4(4-(Furan-2-yl)-N-isopropylbenzamido)methyl)-4-methylphenoxy)hexanoicacid

The title compound (350 mg) was prepared from2-hydroxy-5-methylbenzaldehyde (2.5 g, 18.38 mmol) using the procedureof Example-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.79 (s, 1H),7.79-7.69 (m, 3H), 7.46 (d, J=7.6 Hz, 2H), 7.08-6.94 (m, 3H), 6.84 (d,J=8.0 Hz, 1H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.50 (s, 2H), 4.15 (br,1H), 3.96 (t, J=6.4 Hz, 2H), 2.25 (m, 5H), 1.78-1.70 (br, 2H), 1.60-1.55(m, 2H), 1.47-1.42 (m, 2H), 1.11 (d, J=6.4 Hz, 6H). LCMS (m/z): 464.3(M+1)⁺. HPLC: 97.47% (210 nm).

Example 28:6-((4(4-(Furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoicacid

a) Synthesis of 2-hydroxy-5-methoxybenzaldehyde

In a 250-mL round bottom flask, a stirred solution of2,5-dimethoxybenzaldehyde (5.0 g, 30.02 mmol) was dissolved in DCM (50mL). Aluminum chloride (18.2 g, 136.8 mmol) was added to the abovesolution at rt under nitrogen atmosphere. The reaction mixture wasstirred at rt for 12 h. Upon completion of the reaction (TLC), thereaction mixture was diluted with cold water and extracted with DCM (100mL×2). The combined organic extract was washed with brine andconcentrated under reduced pressure to get title compound (4.51 g, 98%)as yellow oil. LCMS (m/z): 152.1 (M+1)⁺.

b) Synthesis of6-((4(4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoic acid

The title compound (230 mg) was prepared from2-hydroxy-5-methoxybenzaldehyde (2.5 g, 16.44 mmol) using the procedureof Example-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.81 (s, 1H), 7.75(d, J=6.4 Hz, 3H), 7.45 (d, J=7.6 Hz, 2H), 6.99 (d, J=3.2 Hz, 1H), 6.89(d, J=8.8 Hz, 1H), 6.82-6.72 (m, 2H), 6.61 (m, 1H), 4.51 (s, 2H), 4.14(br, 1H), 3.94 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 2.23 (t, J=7.2 Hz, 2H),1.73 (br, 2H), 1.60-1.57 (m, 2H), 1.50-1.38 (m, 2H), 1.11 (d, J=6.4 Hz,6H). LCMS (m/z): 480.5 (M+1)⁺. HPLC: 95.33% (210 nm).

Example 29:6-(4-Cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 50-mL resealable reaction tube, ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(500 mg, 0.879 mmol) from example 25c was dissolved in degassed DMA (15mL) at rt under nitrogen atmosphere. Pd₂(dba)₃ (21.0 mg, 0.023 mmol), Znpowder (0.126 g, 0.002 mmol) and dppf (14.9 mg, 0.027 mmol) and Zn(CN)₂(62.6 mg, 0.51 mmol) were sequentially added to the above solution undernitrogen atmosphere. The resulting mixture was degassed by purging argongas for 15 min. The reaction mixture was heated to 100° C. and stirredat same temperature until completion of the reaction (TLC). The reactionmixture was cooled to rt, diluted with cold water and extracted withethyl acetate (3×30 mL). The combined organic extract was washed withbrine and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 10-15%EtOAc-hexanes) to afford the title compound (361 mg, 81.8%) as paleyellow solid. LCMS (m/z): 503.2 (M+1)⁺.

b) Synthesis of6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.30 g, 0.597 mmol) was dissolved in THF (4 mL)-water (4 mL) mixture atrt. Lithium hydroxide monohydrate (0.125 g, 2.988 mmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure; residue obtained was diluted with water andacidified with 2N HCl. The aqueous solution was extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was washed with n-pentane and dried under reducedpressure to give the title compound (0.150 g, 53%) as pale yellow solid.¹H NMR (400 MHz, DMSO-d6, 60° C.) δ 11.80 (s, 1H), 7.77-7.75 (m, 3H),7.70 (dd, J=8.4, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.51 (d, J=7.6 Hz,2H), 7.17 (d, J=8.8 Hz, 1H), 7.00 (d, J=3.2 Hz, 1H), 6.62 (dd, J=3.6,1.6 Hz, 1H), 4.52 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz,2H), 1.81-178 (m, 2H), 1.62-159 (m, 2H), 1.50-1.47 (m, 2H), 1.12 (d,J=6.4 Hz, 6H). LCMS (m/z): 475.2 (M+1)⁺. HPLC: 95.98% (210 nm).

Example 30:6-((4(4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-(((2,2,2-trifluoroethyl)amino)methyl)phenoxy)hexanoate

To a stirred solution of ethyl 6-(2-formylphenoxy)hexanoate (0.50 g,1.89 mmol) in 1,2-dichloroethane (50 mL), 2,2,2-trifluoroethanamine(0.21 g, 2.12 mmol) and acetic acid (0.85 g, 124.74 mmol) were added atrt under nitrogen atmosphere. The mixture was stirred at rt for 30 minand treated with NaBH(OAc)₃ (0.9 g, 12.47 mmol) under nitrogenatmosphere. The reaction mixture was stirred at rt for 3h. Uponcompletion of the reaction (TLC), the reaction mixture was quenched withsaturated NaHCO₃and extracted with ethyl acetate (50 mL×2). The combinedorganic extract was washed with water, brine, dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure to give thetitle compound (0.61 g), which was used in the next step without furtherpurification. LCMS (m/z): 348.3 (M+1)⁺.

b) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution ethyl6-(2-(((2,2,2-trifluoroethyl) amino)methyl)phenoxy)hexanoate (0.55 g,1.58 mmol) in DCM (30 mL) was treated with 4-(furan-2-yl)benzoylchloride (0.3 g, 1.4 mmol) [prepared by reaction of4-(furan-2-yl)benzoic acid (0.3 g) and thionyl chloride (2 mL) at rt for12h] and Et₃N (0.431 mL, 3.17 mmol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 2 h under nitrogen atmosphere.Upon completion of the reaction (TLC), the reaction mixture was dilutedwith cold water (10 mL) and extracted with DCM (30 mL×2). The combinedorganic extract was washed with aqueous NaHCO₃, brine and dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureand residue obtained was purified by silica gel column chromatography(elution 50% EtOAc-hexanes) to give title compound (0.351 g, 42.9%).LCMS (m/z): 540.2 (M+Na)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoic acid

A stirred solution of ethyl6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoate (0.10 g, 0.193 mmol) in THF (5 mL), EtOH (3 mL)and water (2 mL) was treated with lithium hydroxide monohydrate (0.04 g,0.96 mmol) at rt. The mixture was stirred at 90° C. for 3 h. Uponcompletion of the reaction (TLC), the solvent was removed under reducedpressure. The residue obtained was washed with EtOAc and n-pentane. Theresidue was dissolved in water and the solution acidified with 2 N HCl.The aqueous solution was extracted with EtOAc (25 mL×3). The combinedorganic extract was dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to give the title compound (0.025 g, 62.8%). ¹H NMR(400 MHz, DMSO-d₆, 80° C.): δ 7.75 (d, J=8.0 Hz, 3H), 7.46 (d, J=8.0 Hz,2H), 7.26 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.02-6.87 (m, 3H),6.60 (dd, J=3.2, 1.6 Hz, 1H), 4.68 (s, 2H), 4.18 (q, J=9.6 Hz, 2H), 3.95(t, J=6.4 Hz, 2H), 2.01 (br t, J=7.2 Hz, 2H), 1.69-1.65 (m, 2H),1.56-1.50 (m, 2H), 1.39-1.34 (m, 2H). LCMS (m/z): 540.2 (M+1)⁺. HPLC:95.11% (210 nm).

Example 31:6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl 6-(2-((methylamino)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a solution of methyl amine hydrochloride(0.515 g, 7.62 mmol) in MeOH (15 mL) was treated with Et₃N (1.03 mL, 7.5mmol) at rt. The mixture was stirred at rt for 15 min and treated with asolution ethyl 6-(2-formylphenoxy)hexanoate (0.5 g, 1.89 mmol) in MeOH(15 mL) at rt under nitrogen atmosphere. The resulting mixture wasstirred at rt for 1 h. The mixture was cooled to 0° C. and NaBH₄ (0.037g, 0.99 mmol) was added in portions at rt. The reaction mixture wasstirred at rt for 1 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure. The residueobtained was diluted with cold water and extracted with EtOAc (30 mL×2).The combined organic extract was washed with brine and dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureto afford the title compound (0.408 g), which was used in the next stepwithout further purification. LCMS (m/z): 280.1 (M+1)⁺.

b) Synthesis of ethyl6-((4(4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy) hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((methylamino)methyl)phenoxy)hexanoate (0.4 g, 1.43 mmol) and4-(furan-2-yl)benzoic acid (0.323 g, 1.72 mmol) in DMF (20 mL) wastreated with EDCI.HCl (0.546 g, 2.86 mmol), HOBt (0.388 g, 2.86 mmol)and Et₃N (0.778 mL, 5.72 mol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 12 h under nitrogen atmosphere.Upon completion of reaction (TLC), the reaction mixture was diluted withcold water, and extracted with EtOAc (30 mL×2). The combined organicextract was washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (elution, 20%EtOAc-hexanes) to yield the title compound (0.399 g, 62.1%). LCMS (m/z):472.1 (M+Na)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic acid

To a stirred solution of ethyl6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy) hexanoate (0.200g, 0.44 mmol) in THF (10 mL), EtOH (8 mL) and water (5 mL), was treatedwith lithium hydroxide monohydrate (0.092 g, 2.20 mmol) at rt. Themixture was stirred at 90° C. for 3 h. Upon completion of reaction(TLC), the reaction mixture was concentrated under reduced pressure. Theresidue was washed with EtOAc, diluted with cold water and acidifiedwith 2N HCl. The aqueous layer was extracted with EtOAc (25 mL×3). Thecombined organic extract was washed with brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure to give thetitle compound (0.110 g, 59.5%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ11.76 (s, 1H), 7.79-7.68 (m, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.6Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.04-6.93 (m, 3H), 6.60 (br, 1H), 4.58(br s, 2H), 3.98 (br, 2H), 2.90 (s, 3H), 2.20 (t, J=7.2 Hz, 2H),1.72-1.63 (m, 2H), 1.62-1.51 (m, 2H), 1.48-1.29 (m, 2H). LCMS (m/z):422.0 (M+1)⁺. HPLC: 96.89% (210 nm).

Example 32: Synthesis of6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoicacid

a) Synthesis of ethyl 6-(2-((isopropylamino)methyl-d)phenoxy)hexanoate

In a 100-mL round bottom flask, isopropyl amine (2.70 g, 45.7 mmol) andethyl 6-(2-formylphenoxy)hexanoate (10 g, 37.8 mmol) from example 1(b)are dissolved in 1,2-dichloroethane (50 mL) at rt. Sodiumcyanoborodeuteride (17.8 g, 83.9 mmol) is added slowly in portions atrt. The reaction mixture is stirred at rt under nitrogen atmosphere. Thereaction mixture is quenched by adding saturated sodium carbonatesolution, and is extracted with ethyl acetate. The ethyl acetate extractis washed with brine and dried over anhydrous Na₂SO₄. The solution isconcentrated under reduced pressure to give title compound.

b) Synthesis of ethyl6-(2-((6-chloro-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoate

The title compound is prepared from ethyl6-(2-((isopropylamino)methyl-d)phenoxy)hexanoate using the method ofexample 1(c).

c) Synthesis of ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoate

The title compound is prepared from ethyl6-(2-((6-chloro-N-sopropylnicotinamido)methyl-d)phenoxy)hexanoate usingthe method of example 1(d).

d) Synthesis of6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d)phenoxy) hexanoicacid

The title compound is prepared from ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl-d)phenoxy)hexanoateusing the method of example 1 (e).

Example 33: Synthesis of6-(2-((6-(furan-2-yl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoicacid

a) Synthesis of 2-((propan-2-ylideneamino)methyl)phenol

A solution of 2-(aminomethyl)phenol in acetone is heated to reflux for 4hours. After cooling to room temperature, the solution is dried overNa₂SO₄ and concentrated under reduced pressure to leave the titlecompound.

b) Synthesis of ethyl6-(2-((propan-2-ylideneamino)methyl)phenoxy)hexanoate

The title compound is prepared from2-((propan-2-ylideneamino)methyl)phenol using the method of example1(a).

c) Synthesis of ethyl6-(2-(((propan-2-yl-2-d)amino)methyl)phenoxy)hexanoate

In a round bottom flask, ethyl6-(2-((propan-2-ylideneamino)methyl)phenoxy)hexanoate is dissolved in1,2-dichloroethane at rt. Sodium cyanoborodeuteride is added slowly inportions at rt. The reaction mixture is stirred at rt under nitrogenatmosphere. The reaction mixture is quenched by adding saturated sodiumcarbonate solution, and is extracted with ethyl acetate. The ethylacetate extract is washed with brine and dried over anhydrous Na₂SO₄.The solution is concentrated under reduced pressure to give titlecompound.

d) Synthesis of ethyl6-(2-((6-chloro-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoate

The title compound is prepared from ethyl6-(2-(((propan-2-yl-2-d)amino)methyl)phenoxy)hexanoate using the methodof example 1(c).

e) Synthesis of ethyl6-(2-((6-(furan-2-yl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoate

The title compound is prepared from ethyl6-(2-((6-chloro-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoateusing the method of example 1(d).

f) Synthesis of6-(2-((6-(furan-2-yl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoicacid

The title compound is prepared from ethyl6-(2-((6-(furan-2-yl)-N-(propan-2-yl-2-d)nicotinamido)methyl)phenoxy)hexanoateusing the method of example 1 (e).

Example 13 Pharmacokinetics

In this example, the PK profile of several PPARδ agonists disclosedherein in male CD-1 mice or Wistar rats was determined. Similar methodscan be used to analyze other compounds provided herein.

Compounds 12 and 176 were dissolved in 2% dimethylacetamide (DMA) and20% 2-hydroxypropyl-beta-cyclodextrin (HPβCD) q.s. Compound 245 andGW501516 were dissolved in 5% ethanol and 5% solutol in purified waterq.s. (quantity sufficient ie made up to a final volume of 100% withwater). All compounds were separately administered to CD-1 mice at 3mg/kg iv or 10 mg/kg po. GW501516 was administered to Wistar rats at 3mg/kg (i.v.) or 10 mg/kg (p.o.).

The concentration of the compound in plasma was determined, asillustrated in FIGS. 9A-9E.

Experimental parameters for compound 12 are provided in Tables 2A and2B, with in vitro parameters and data provided in Table 2C.

TABLE 2A Intravenous PK parameters Beta K_(el) T_(1/2) AUC_((0-inf)) C₀V_(z) V_(ss) Cl MRT Parameters (hr−1) (hr) (hr*ng/mL) (ng/mL) (L/kg)(L/kg) (mL/hr/kg) (hr) 3 mg/Kg 3.85 0.18 256.5 1938.2 3.03 1.58 1169.30.12

TABLE 2B Oral PK parameters Parameters AUC_((0-inf)) T_(max) C_(max)T_(1/2) F (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 187.0 0.50 128.7 2.60~22

TABLE 2C In vitro parameters/data Solubility (μM) Kinetic 6Thermodynamic 253 % Parent remained at 15/60 min MLM 59/19 HLM 92/64Potency (cell based) PPAR delta 4.8 EC₅₀ (nM) NHR ptn interaction assay

Experimental parameters for compound 176 are provided in Tables 3A and3B, with in vitro parameters and data provided in Table 3C.

TABLE 3A Intravenous PK parameters Beta K_(el) T_(1/2) AUC_((0-inf)) C₀V_(z) V_(ss) Cl MRT Parameters (hr−1) (hr) (hr*ng/mL) (ng/mL) (L/kg)(L/kg) (mL/hr/kg) (hr) 3 mg/Kg 0.41 1.68 1134.7 7056.5 6.42 1.64 2643.80.47

TABLE 3B Oral PK parameters Parameters AUC_((0-inf)) T_(max) C_(max)T_(1/2) F (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 943.8 0.25 1111.7 2.68~25.0

TABLE 3C In vitro parameters/data Solubility (μM) Kinetic 191Thermodynamic 506 % Parent remained at 15/60 min MLM  78/56 HLM 100/73Potency (cell based) PPAR delta 12.6 EC₅₀ (nM) NHR ptn interaction assay

Experimental in vitro parameters and data for compound 237 are providedin Table 4.

TABLE 4 Solubility (μM) Kinetic 146 Thermodynamic 88 % Parent remainedat 15/60 min MLM 88/60 HLM 77/38 Potency (cell based) PPAR delta 11 nMEC₅₀ (nM) NHR ptn interaction assay

Experimental parameters for compound GW501516 administered to maleWistar rats are provided in Tables 5A and 5B, with in vitro parametersand data provided in Table 5C.

TABLE 5A Intravenous PK parameters Beta K_(el) T_(1/2) AUC_((0-inf)) C₀V_(z) V_(ss) Cl MRT Parameters (hr−1) (hr) (hr*ng/mL) (ng/mL) (L/kg)(L/kg) (mL/hr/kg) (hr) 3 mg/Kg 0.09 8.07 9960.0 5277.8 3.58 1.99 305.94.30

TABLE 5B Oral PK parameters Parameters AUC_((0-inf)) T_(max) C_(max)T_(1/2) F (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 35121.0 2.00 6920.06.21 ~100

TABLE 5C In vitro parameters/data Solubility (μM) Kinetic 195Thermodynamic 246 % Parent remained at 15/60 min MLM 93/76 Potency (cellbased) PPAR delta 2 nM EC₅₀ (nM) trans activation

Experimental parameters for compound GW501516 administered to CD-1 miceare provided in Tables 6A and 6B, with in vitro parameters and dataprovided in Table 6C.

TABLE 6A Intravenous PK parameters Beta Kel T½ AUC (0-inf) C0 Vz Vss ClMRT Parameters (hr−1) (hr) (hr*ng/mL) (ng/mL) (L/kg) (L/kg) (mL/hr/kg)(hr) 3 mg/Kg 0.11 6.44 11319.1 5560.5 2.46 1.71 265.0 4.96

TABLE 6B Oral PK parameters Parameters AUC_((0-inf)) T_(max) C_(max)T_(1/2) F (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 30990.7 2.00 3293.35.98 82.1

TABLE 6C In vitro parameters/data Solubility (μM) Kinetic 195Thermodynamic 246 % Parent remained at 15/60 min MLM 93/76 Potency (cellbased) PPAR delta 2 nM EC₅₀ (nM) trans activation

Example 14

The following examples provide physical and in vitro data for variousdifferent exemplary compounds.

Nuclear Hormone Receptor (NHR) Assays

Cell Handling: PathHunter NHR cell lines were expanded from freezerstocks according to standard procedures. Cells were seeded in a totalvolume of 20 μL into white walled, 384-well microplates and incubated at37° C. for the appropriate time prior to testing. Assay media containedcharcoal-dextran filtered serum to reduce the level of hormones present.Agonist Format: For agonist determination, cells were incubated withsample to induce response. Intermediate dilution of sample stocks wasperformed to generate 5× sample in assay buffer. 5 μL of 5× sample wasadded to cells and incubated at 37° C. or room temperature for 3-16hours. Final assay vehicle concentration was 1%.Antagonist Format: For antagonist determination, cells werepre-incubated with antagonist followed by agonist challenge at the EC₈₀concentration. Intermediate dilution of sample stocks was performed togenerate 5× sample in assay buffer. 5 μL of 5× sample was added to cellsand incubated at 37° C. or room temperature for 60 minutes. Vehicleconcentration was 1%. 5 μL of 6×EC₈₀ agonist in assay buffer was addedto the cells and incubated at 37° C. or room temperature for 3-16 hours.

Signal Detection: Assay signal was generated through a single additionof 12.5 or 15 μL (50% v/v) of PathHunter Detection reagent cocktail,followed by a one hour incubation at room temperature. Microplates wereread following signal generation with a PerkinElmer Envision™ instrumentfor chemiluminescent signal detection.

Data Analysis: Compound activity was analyzed using CBIS data analysissuite (ChemInnovation, CA). For agonist mode assays, percentage activitywas calculated using the following formula:

% Activity=100%×(mean RLU of test sample−mean RLU of vehiclecontrol)/(mean MAX control ligand−mean RLU of vehicle control).

For antagonist mode assays, percentage inhibition was calculated usingthe following formula:

% Inhibition=100%×(1−(mean RLU of test sample−mean RLU of vehiclecontrol)/(mean RLU of EC₈₀ control−mean RLU of vehicle control)).

Note that for select assays, the ligand response produces a decrease inreceptor activity (inverse agonist with a constitutively active target).For those assays inverse agonist activity was calculated using thefollowing formula:

% Inverse Agonist Activity=100%×((mean RLU of vehicle control−mean RLUof test sample)/(mean RLU of vehicle control−mean RLU of MAX control)).

TABLE 7 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 127 467 5.57 44.6 176 421 4.68 12.6 247 447 5.49 10.54 12 447 5.274.8 247 497 6.45 18.8

TABLE 8 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 126 413 4.47 1298.5 127 467 5.5744.6 129 425 3.96 5071.10 130 461 3.03 >10000 237 447 5.49 10.54 132 4014.47 2184.70 151 408 3.85 894.3 135 449 5.31 3151.9 136 450 4.58 351.8134 437 4.80 95.5 133 497 3.67

TABLE 9 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 152 485 5.83 >10000 153 450 4.42206.4 154 453 5.51 21.3 155 450 4.63 26.1 156 456 4.46 142.9 157 4495.82 >10000 158 449 5.60 >10000 160 467 5.75 159 467 5.75

TABLE 10 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 176 421 4.68 12.6 178 465 5.0 79.4177 489 5.48 12.1 179 407 4.71 485.11 180 463 5.02

TABLE 11 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 202 547 6.53 7.3 203 463 6.02 7.1204 467 5.81 24.6 205 474 5.28 223.6 206 479 5.61 5.1 207 450 4.92 19.4208 450 4.53

TABLE 12 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 219 459 5.01 338.5 220 463 5.98511.8 221 451 4.75 1295.1 225 451 4.43 392.3 226 435 5.00 112.9 227 4643.68 231 462 2.6

TABLE 13 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 248 419 4.65 21.1

TABLE 14 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 125 417 5.03 291.4 126 413 4.471298.5 127 467 5.57 44.6 128 426 4.72 5390.50 129 425 3.96 5071.10 130461 3.03 >10000 131 397 4.75 1609.50 245 447 5.49 10.54 132 401 4.472184.70 151 408 3.85 894.3 135 449 5.31 3151.9 136 450 4.58 351.8 134437 4.80 >10000

TABLE 15 NHR protein PPARd, interaction assay, Compd EC₅₀ (nM) EC₅₀ (nM)for No MW ClogP (from Salk) PPARδ 57 459 6.14 42 25.9 37 463 6.05 4117.5 61 449 5.52 9 5.9 62 449 5.3 61 36.8 63 465 6.0 ND 8.4 64 465 5.8117.2 8.02 12 447 5.27 19.6 4.8 28 497 6.45 290 18.8 267 469 5.02 19.65.0

TABLE 16 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 127 467 5.57 44.6 176 421 4.68 12.6 245 447 5.49 10.54 12 447 5.274.8 247 497 6.45 18.8

Example 15 GW Treatment Prevents the Accumulation of VLCFAs by InducingMitochondrial FA Oxidation in a Mouse Model of ALD

As GW treatment dramatically induced mitochondrial fatty acid (FA)oxidation and reduced fat accumulation, GW was evaluated to see if couldimprove FA metabolism disorders such as ALD. ALD is a rare geneticdisorder caused by defects in peroxisomal oxidation of very long-chainfatty acids (VLCFAs), resulting in systemic accumulation of VLCFAs,which causes tissue defects mainly in the central nervous system and theadrenal glands. The majority of VLCFAs in the body are endogenouslysynthesized from long-chain fatty acids (LCFAs). Therefore, onepotential way to prevent VLCFA accumulation in ALD is by inducingmitochondrial LCFA oxidation to reduce the availability of LCFAs forVLCFA biosynthesis. In order to test this, a previously described mousemodel of ALD was used, in which the X-linked adrenoleukodystrophy geneabcd1 was systemically ablated and the knockout (AKO) mice faithfullyrecapitulated the abnormal VLCFA accumulation phenotype seen in ALDpatients.

3-month-old AKO mice were treated with or without GW and their tissuescollected for free FA analysis using GC/MS. Similar to what waspreviously reported, both brain and liver from AKO mice had greatlyincreased levels of VLCFAs including C22:0, C23:0, C24:0, and C26:0,while the levels of total FAs (C12-C26) remained unaffected (FIGS. 10Aand 10B). After 8 weeks of GW treatment, the levels of all four VLCFAsin AKO brain and liver were significantly reduced, with all liver C26:0cleared in most GW-treated animals (FIGS. 10A and 10B). Without beingbound to a particular theory, the reduction of VLCFAs may be due toGW-induced mitochondrial FA oxidation in peripheral tissues, since GWtreatment dramatically induced the expression of mitochondrial FAoxidation genes including Cpt1a and 1 b, Slc25a20, and Acadl in AKOliver and skeletal muscle (FIGS. 11A and 11B), which was furthersupported by the fact that most saturated LCFAs including C12:0 to C22:0and the total FAs were significantly reduced by GW treatment in bothliver and muscle (FIGS. 12A, 12B and 10B).

While the disclosure has been described and illustrated with referenceto certain embodiments thereof, those having ordinary skill in the artwill appreciate that various changes, modifications, and substitutionscan be made therein without departing from the spirit and scope of thepresent disclosure. For example, effective dosages other than thedosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forPPARδ-related disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentdisclosure. Accordingly, the disclosure is not to be limited as by theappended claims.

The features disclosed in this description and/or in the claims may bothseparately and in any combination thereof be material for realizing thedisclosure in diverse forms thereof.

In view of the many possible embodiments to which the principles of thedisclosure may be applied, it should be recognized that the illustratedembodiments are only examples of the invention and should not be takenas limiting the scope of the invention. Rather, the scope of thedisclosure is defined by the following claims. We therefore claim as ourinvention all that comes within the scope and spirit of these claims.

We claim:
 1. A compound having a formula,

wherein: ring A is phenyl; ring B is selected from phenyl, or pyridine;each R² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl; each R²² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl; n is from 0 to 5; m is from 0 to 4; X is O, NR³⁰, sulfonyl, or S;each R³⁰ independently is selected from H or aliphatic, aryl, orcycloaliphatic; each L² is selected from a bond, aliphatic,heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴; R²³ and R²⁴ are each independentlyselected from H, deuterium, halogen, aliphatic, alkyl, —C(O)OR²⁵ or—C(O)NR²⁵R²⁶; R²⁵ and R²⁶ are each independently selected from hydrogenor aliphatic; Z is R¹L^(1C)(O)—; L¹ is a bond or —NR³⁰—; R¹ is hydrogen,aliphatic, —OR^(1A), —NR^(1A)R^(1B), —C(O)R^(1A), —S(O)₂R^(1A),C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or —C(O)NR^(1A)R^(1B); R^(1A), R^(1B)are each independently selected from hydrogen or aliphatic; p is 0, 1,2, or 3; p′ is 0; L⁴ is selected from a bond, aliphatic,heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴; R³ is selected from —OH,—NR^(3A)R^(3B), —C(O)R^(3A), —S(O)₂R^(3A), —C(O)OR^(3A),—S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B), aliphatic, heteroaliphatic,cycloalkyl, heterocycloalkyl, aryl, heteroaryl; and R^(3A) and R^(3B)are independently selected from hydrogen or aliphatic; R³¹ and R³² areindependently H, D, or aliphatic; with the provisos that at least one ofL⁴ or R³ comprises at least one deuterium; or at least one of R³¹ andR³² is D.
 2. The compound according to claim 1, wherein L⁴R³ isisopropyl

cyclopropyl, or


3. The compound of claim 1, wherein ring B is phenyl.
 4. The compound ofclaim 1, wherein L² is


5. The compound of claim 1, wherein p is
 1. 6. The compound of claim 5,wherein each of R³¹ and R³² is independently H or D.
 7. The compound ofclaim 1, wherein Z is CO₂H.
 8. The compound of claim 1, wherein at leastone of L⁴ or R³ comprises at least one deuterium.
 9. The compound ofclaim 1 wherein X is O.
 10. The compound of claim 1, wherein each R²independently is selected from methyl, trifluoromethyl, methoxy,trifluoromethoxy, dimethylamino, acetyl, methanesulfonyl, cyano,cyclopropoxy, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,3-pyridyl, 4-pyridyl, pyrrolidin-1-yl,


11. The compound of claim 1, wherein n is 1 and R² is heteroaryl. 12.The compound of claim 1, wherein R² is furan-2-yl or furan-3-yl.
 13. Thecompound according to claim 1, wherein the compound has a formula

wherein: each R² independently is selected from deuterium, halogen,aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH,amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl,SO₃H, or acyl; each R²² independently is selected from deuterium,halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic,NO₂, OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester,alkylsulfonyl, SO₃H, or acyl; n is from 0 to 5; m is from 0 to 4; X isO, NR³⁰, sulfonyl, or S; each R³⁰ independently is selected from H oraliphatic, aryl, or cycloaliphatic; each L² is selected from a bond,aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴—; R²³ and R²⁴ are each independentlyselected from H, deuterium, halogen, aliphatic, alkyl, —C(O)OR²⁵ or—C(O)NR²⁵R²⁶; R²⁵ and R²⁶ are each independently selected from hydrogenor alkyl; L¹ is a bond or —NR³⁰—; R¹ is hydrogen, aliphatic, —OR^(1A),—NR^(1A)R^(1B), —C(O)R^(1A), —S(O)₂R^(1A), —C(O)OR^(1A),—S(O)₂NR^(1A)R^(1B) or —C(O)NR^(1A)R^(1B); R^(1A), R^(1B) are eachindependently selected from hydrogen or aliphatic; L³ is selected from abond or C₁₋₃aliphatic; L⁴ is selected from a bond, aliphatic,heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴—; R³ is selected from —OH, —OR^(3A),—NR^(3A)R^(3B), —C(O)R^(3A), —S(O)₂R^(3A), —C(O)OR^(3A),—S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B), aliphatic, heteroaliphatic,cycloalkyl, heterocycloalkyl, aryl, heteroaryl; and R^(3A) and R^(3B)are independently selected from hydrogen or aliphatic; with the provisosthat at least one of L³, L⁴ or R³ comprises at least one deuterium. 14.The compound of claim 13, wherein at least one of L⁴ or R³ comprises atleast one deuterium.
 15. The compound of claim 13, wherein L³ is —CHD-or -CD₂-.
 16. The compound of claim 15, wherein L³ is —CHD-.
 17. Thecompound of claim 13, wherein each R² independently is selected frommethyl, trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino,acetyl, methanesulfonyl, cyano, cyclopropoxy, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, 3-pyridyl, 4-pyridyl, pyrrolidin-1-yl,


18. The compound of claim 13, wherein n is 1 and R² is heteroaryl. 19.The compound of claim 13, wherein R² is furan-2-yl or furan-3-yl.
 20. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound according to claim 1.